CN104341471B

CN104341471B - Macrolides compound or its salt, synthetic method, pharmaceutical composition and its application

Info

Publication number: CN104341471B
Application number: CN201410273320.4A
Authority: CN
Inventors: 沈舜义; 陈代杰; 张志宏; 任岩松; 李继安; 李忠磊; 张芸; 徐屹军; 樊钱永; 葛涵
Original assignee: Shanghai Institute of Pharmaceutical Industry; China State Institute of Pharmaceutical Industry
Current assignee: Shanghai Institute of Pharmaceutical Industry; China State Institute of Pharmaceutical Industry
Priority date: 2013-07-30
Filing date: 2014-06-18
Publication date: 2019-01-22
Anticipated expiration: 2034-06-18
Also published as: CN104341471A; CN104337826A; CN104337826B

Abstract

The invention discloses macrolides compound or its salt, synthetic method, pharmaceutical composition and its applications.The present invention provides a kind of macrolides compound 1, macrolides compound 1 ' or its salt, containing its pharmaceutical composition and they preparation inhibit methicillin-resistant staphylococcus aureus drug in application.Macrolides compound 1 of the invention, macrolides compound 1 ', the salt of macrolides compound 1 and macrolides compound 1 ' one of salt or a variety of when being used in conjunction with beta-lactam antibiotic, can significantly increase the effect that beta-lactam antibiotic inhibits methicillin-resistant staphylococcus aureus.This is a kind of Novel synergistic agent, and external synergistic effect is good, can alleviate methicillin-resistant staphylococcus aureus (MRSA) to the drug resistance of beta-Lactam antibiotic, be a kind of drug with the good prospect of marketing.

Description

Macrolides compound or its salt, synthetic method, pharmaceutical composition and its application

Technical field

The present invention relates to macrolides compound or its salt, synthetic method, pharmaceutical composition and its applications.

Background technique

In recent years, a new upsurge is entered to the research and development of third generation macrolide antibiotic, in big ring Ester antibiotic action target spot --- ribosomes 50S subunit structure and macrolide antibiotic and ribosomes 50S subunit bound site Deepening continuously for point and different combination research, will provide for the research and development with novel structure macrolide antibiotic More theoretical foundations and support.In addition, the diversity of Macrocyclic lactone compounds and ribosome bind site and combination, is it Pharmacological action and novel clinical use other than antibacterial action provide part foundation.

Overcome clinical methicillin-resistant staphylococcus aureus to generate the defect of drug resistance to beta-lactam antibiotic, opens Sending does not easily cause bacterial drug resistance, antibacterial action, and good antibiotic has great importance.

Summary of the invention

The technical problem to be solved by the present invention is in order to overcome clinical methicillin-resistant staphylococcus aureus interior to β- Amides antibiotic generates the defect of drug resistance, and provides macrolides compound or its salt, synthetic method, pharmaceutical composition Object and its application.It is of the invention with macrolides compound and/or its salt when being used in conjunction with beta-lactam antibiotic, The effect that beta-lactam antibiotic inhibits methicillin-resistant staphylococcus aureus can significantly be increased.

The present invention provides a kind of macrolides compound 1, compound 1 ' or its salt,

Wherein, R₁ForR₂For hydrogen；R₃For methyl；R₄For methoxyl group or hydroxyl；R₅ForHydrogen orR₆For hydroxyl；R₇For hydroxyl；R₈For selected from hydrogen, halogen (fluorine, chlorine, bromine or iodine, it is excellent Select fluorine or chlorine), substituted or unsubstituted C₁~C₄Alkyl (" the substituted C₁~C₄Alkyl " described in be substituted by Replaced one or more of fluorine, chlorine or bromine, " the substituted C₁~C₄Alkyl " preferred trifluoromethyl；Described " substituted or unsubstituted C₁~C₄Alkyl " described in " C₁~C₄Alkyl " can for methyl, ethyl, propyl, isopropyl, Butyl, isobutyl group or tert-butyl) and C₁~C₄Alkoxy (preferably methoxyl group, ethyoxyl, propoxyl group or isopropoxy) in one It is a or multiple, work as R₈When for multiple substituent groups, each substituent group can be identical or different；R₁₇For C₁~C₄Alkyl acyl is (preferablyR₁₀For hydrogen, substituted or unsubstituted C₁~C₄Alkyl (" the substituted or unsubstituted C₁~C₄Alkyl " in " the C₁~C₄Alkyl " such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tert-butyl, preferably methyl, second Base, isobutyl group；The R₁₀Described in " substituted or unsubstituted C₁~C₄Alkyl " described in " substitution " be quiltReplaced, wherein X is C or N, R₁₆For hydrogen, C₁~C₄Alkyl (such as methyl, ethyl, propyl or isopropyl Base) and C₁~C₄One or more of alkoxy (such as methoxyl group, ethyoxyl, propoxyl group or isopropoxy), work as R₁₆Table When showing multiple substituent groups, substituent group can be identical or different；" the substituted C₁~C₄Alkyl " preferablySubstituted or unsubstituted phenyl (" substitution " described in " the substituted phenyl " is to be selected from phenyl, C by one or more₁~C₄Alkoxy (preferably first Oxygroup), halogen (fluorine, chlorine, bromine or iodine, preferably fluorine), nitro and C₁~C₄Alkyl (preferably methyl, ethyl or propyl) substitution Replaced base；" the substituted phenyl " preferably xenyl, 4- methoxyphenyl, 4- fluorophenyl, 4- chlorphenyl o-hydroxy Base, m-nitro base, 2,5- difluorophenyl or hydroxy phenyl；The xenyl can beC₄ ~C₅(preferably hetero atom is oxygen, sulphur or nitrogen, the C that hetero atom number is 1 to heteroaryl₄~C₅Heteroaryl, described " hetero atom is Oxygen, sulphur or nitrogen, the C that hetero atom number is 1₄~C₅Heteroaryl " preferably pyridyl group, thienyl, furyl or pyrrole radicals；Described The preferred 2- pyridyl group of pyridyl group, the preferred 2- thienyl of the thienyl, the preferred 2- furyl of the furyl, the pyrrole Cough up the preferred 2- pyrrole radicals of base) or R₁₀With R₁₅Be connected to become 3-6 membered cyclic structure (preferably 5 membered cyclic structures, such as R₁₃For hydroxyl orR₁₄It is substituted or unsubstituted phenyl (described in " the substituted or unsubstituted phenyl " " substitution " be replaced one or more substituent groups selected from methoxyl group, ethyoxyl, propoxyl group and isopropoxy, it is described " substituted phenyl " preferably 4- methoxyphenyl) or C₁~C₄Alkyl (preferably methyl, ethyl, propyl, isopropyl, butyl, Isobutyl group or tert-butyl)；R₁₅For hydrogen or C₁~C₄Alkyl (preferably methyl or ethyl).

In the present invention, in the compound as shown in Equation 1, it is preferable that R₁ForR₂For hydrogen；R₃ For methyl；R₄For methoxyl group or hydroxyl；R₅ForHydrogen orR₆For hydroxyl；R₇For hydroxyl；R₈For selected from Hydrogen, halogen (fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine), substituted or unsubstituted C₁~C₄Alkyl (" the substituted C₁~ C₄Alkyl " described in be substituted by replaced one or more of fluorine, chlorine or bromine, " the substituted C₁~C₄Alkane The preferred trifluoromethyl of base "；" the substituted or unsubstituted C₁~C₄Alkyl " described in " C₁~C₄Alkyl " can be Methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tert-butyl) and C₁~C₄Alkoxy (preferably methoxyl group, ethyoxyl, One or more of propoxyl group or isopropoxy), work as R₈When indicating multiple substituent groups, each substituent group can be identical or different； R₁₇For C₁~C₄Alkyl acyl is (preferablyR₁₀For hydrogen, C₁~C₄Alkyl (such as methyl, ethyl, propyl, isopropyl, Butyl, isobutyl group or tert-butyl, preferably methyl or ethyl), substituted or unsubstituted phenyl (institute in " the substituted phenyl " " substitution " stated is to be selected from phenyl, C by one or more₁~C₄Alkoxy (preferably methoxyl group), halogen (fluorine, chlorine, bromine or iodine, It is preferred that fluorine), nitro and C₁~C₄Alkyl (preferably methyl, ethyl or propyl) substituent group replaced；" the substituted benzene Base " preferably xenyl, 4- methoxyphenyl, 4- fluorophenyl or 4- chlorphenyl；The xenyl can beOr C₄~C₅(preferably hetero atom is oxygen, sulphur or nitrogen, the C that hetero atom number is 1 to heteroaryl₄~C₅Heteroaryl Base, described " hetero atom is oxygen, sulphur or nitrogen, the C that hetero atom number is 1₄~C₅Heteroaryl " preferably thienyl, furyl or pyrrole Cough up base；The preferred 2- thienyl of the thienyl, the preferred 2- furyl of the furyl, the preferred 2- pyrroles of the pyrrole radicals Base)；R₁₅For C₁~C₄Alkyl (preferably methyl or ethyl)；

It is described as in 1 ' compound represented of formula, it is preferable that R in the present invention₁For R₂For hydrogen；R₃For methyl；R₄For methoxyl group or hydroxyl；R₆For hydroxyl；R₇For hydroxyl；R₁₀For hydrogen, substituted or unsubstituted C₁~C₄ Alkyl (" the unsubstituted C₁~C₄Alkyl " such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tertiary fourth Base, preferably methyl, ethyl, isobutyl group；" the substituted C₁~C₄Alkyl " described in " substitution " be quiltReplaced, wherein X is C or N, R₁₆For hydrogen or C₁~C₄Alkyl (preferably methyl)；" the substituted C₁ ~C₄Alkyl " preferably Replace or (" substitution " described in " the substituted phenyl " is to be selected from phenyl, C by one or more to unsubstituted phenyl₁~C₄Alkane Oxygroup (preferably methoxyl group), halogen (fluorine, chlorine, bromine or iodine, preferably fluorine), nitro and C₁~C₄Alkyl (preferably methyl, ethyl or Propyl) substituent group replaced；" the substituted phenyl " preferably xenyl, 4- methoxyphenyl, o-hydroxy-phenyl, nitre Base phenyl, 2,5- difluorophenyl or hydroxy phenyl；The xenyl can beC₄~C₅Heteroaryl (preferably hetero atom is oxygen, sulphur or nitrogen, the C that hetero atom number is 1₄~C₅Heteroaryl, described " hetero atom is oxygen, sulphur or nitrogen, miscellaneous The C that atomicity is 1₄~C₅Heteroaryl " preferably pyridyl group or pyrrole radicals；The preferred 2- pyrrole radicals of the pyrrole radicals, the pyrrole The preferred 2- pyridyl group of piperidinyl) or R₁₀With R₁₅Be connected to become 3-6 membered cyclic structure (preferably 5 membered cyclic structures, such asR₁₄ For substituted or unsubstituted phenyl, (" substitution " described in " the substituted or unsubstituted phenyl " is to be selected by one or more Replaced substituent group from methoxyl group, ethyoxyl, propoxyl group and isopropoxy, " the substituted phenyl " preferably 4- methoxyl group Phenyl) or C₁~C₄Alkyl (preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tert-butyl)；R₁₅For hydrogen or C₁~C₄Alkyl (preferably methyl or ethyl).

In the present invention, the macrolides compound 1 any compound further preferably as follows,

In the present invention, the macrolides compound 1 ' any compound further preferably as follows,

The present invention also provides the preparation methods of the macrolides compound 1, preferably include following steps: will Compound 1-17 carries out alcoholysis reaction, obtains compound 1-18；

Wherein, R₅' beR₅ForR₂、 R₃、R₄、R₆、R₇、R₁₀、R₁₅And R₁₇Definition it is same as above.

In the method for prepare compound 1-18, the alcoholysis reaction can be the normal of such alcoholysis reaction in this field Rule method, particularly preferably following reaction methods and condition in the present invention:

In the method for prepare compound 1-18, the preferred alcohols solvent of the solvent, the preferred first of the alcohols solvent Alcohol and/or ethyl alcohol.

In the method for prepare compound 1-18, the volume mass of the solvent and the compound 1-15 are than preferred 1mL/g~100mL/g, further preferred 1mL/g~20mL/g.

It is preferably 20 DEG C~100 DEG C of the temperature of the alcoholysis reaction, further excellent in the method for prepare compound 1-18 Select 50 DEG C~80 DEG C.

In the method for prepare compound 1-18, the process of the alcoholysis reaction can be using the conventional survey in this field Method for testing (such as TLC, HPLC or NMR) is monitored, as reaction end when generally being disappeared using compound 1-17, preferred reaction time 1 hour~24 hours, further preferred 1 hour~5 hours.

In the method for prepare compound 1-18, following post-processing step is preferably included；After reaction, column chromatography purifies Obtained crude product obtains compound 1-18 after purification.The condition of the column chromatography purifying can use this field In the generic operation conventional method, can be using the mixed solvent of alcohols solvent and halogenated hydrocarbon solvent as eluant, eluent, the alcohol The preferred methanol of class solvent and/or ethyl alcohol；The preferred chlorinated hydrocarbon solvent of the halogenated hydrocarbon solvent, the chlorinated hydrocarbon solvent It is preferred that methylene chloride；The in the mixed solvent alcohols solvent of the alcohols solvent and halogenated hydrocarbon solvent and halogenated hydrocarbon solvent Preferred 1:20~the 20:1 of volume ratio.

In the preparation method of the compound 1-18, following steps are preferably included: in organic solvent, condensing agent Under the conditions of existing, by carboxylic acid R₅OH and/or acid anhydridesCondensation reaction is carried out with compound 1-16, is obtained described Compound 1-17；

Wherein, R₅' beR₂、R₃、R₄、R₆、R₇、R₈、R₁₀、R₁₅And R₁₇Definition It is same as above.

In the preparation method of the compound 1-17, the condensation reaction can be anti-for such condensation in this field The conventional method answered, particularly preferably following reaction methods and condition in the present invention:

In the preparation method of the compound 1-17, the preferred halogenated hydrocarbon solvent of the organic solvent is described The preferred chlorinated hydrocarbon solvent of halogenated hydrocarbon solvent, the preferred methylene chloride of the chlorinated hydrocarbon solvent.

In the preparation method of the compound 1-17, the volume mass ratio of the organic solvent and compound 1-16 It is preferred that 1mL/g~100mL/g, further preferred 1mL/g~20mL/g.

In the preparation method of the compound 1-17, the carboxylic acid R₅OH and/or acid anhydridesWith institute The molar ratio of the compound 1-16 stated preferably 1~3.

In the preparation method of the compound 1-17, preferred 1- ethyl-(the 3- dimethylamino third of the condensing agent Base) carbodiimide hydrochloride (EDCHCl or EDCI, CAS:25952-53-8).

In the preparation method of the compound 1-17, the molar ratio of the condensing agent and the compound 1-16 It is preferred that 1~3.

In the preparation method of the compound 1-17, the preferred 4-dimethylaminopyridine of the catalyst (DMAP, ) or 1- hydroxy benzo triazole (HOBT, CAS:2592-95-2) CAS:1122-58-3.

In the preparation method of the compound 1-17, the molar ratio of the catalyst and the compound 1-16 It is preferred that 0.01~0.1, further preferred 0.01~0.04.

In the preparation method of the compound 1-17, the temperature of the condensation reaction is 10 DEG C~60 DEG C, into one Preferably 15 DEG C~30 DEG C of step.

In the preparation method of the compound 1-17, the process of the condensation reaction can be using in this field Traditional test methods (such as TLC, HPLC or NMR) are monitored, as reaction end when generally being disappeared using compound 1-16, preferably instead 1 hour~24 hours, further preferred 4 hours~10 hours between seasonable.

The preparation method of the compound 1-17 preferably includes following post-processing step: after reaction, adjust pH to 9.0~10.0, extraction, organic phase adds flash column chromatography separation (FLASH pillar layer separation) after methanol eddy after removing solvent, obtains To compound 1-17 after purification.The adjusting pH can use inorganic base, the preferred sodium hydroxide of the inorganic base； The inorganic base can participate in reaction in the form of its aqueous solution, when inorganic base participates in reaction in the form of its aqueous solution, The preferred 3mol/L of the molar concentration of the aqueous solution of the inorganic base, the molar concentration refer to the molal quantity and nothing of inorganic base The ratio of machine aqueous alkali total volume.The extraction can be using the conventional method of extracting operation in this field, the extraction Take the preferred halogenated hydrocarbon solvent of the solvent of use, the preferred chlorinated hydrocarbon solvent of the halogenated hydrocarbon solvent, the chlorohydrocarbon The preferred methylene chloride of class solvent.The flash column chromatography separation (FLASH pillar layer separation) can be using such in this field The conventional method and condition of operation, flash column chromatography separate specification preferably 200 mesh for the silica gel that (FLASH pillar layer separation) uses ~400 mesh silica gel.

In the preparation method of the compound 1-18, following steps are preferably included: in organic solvent, condensing agent Under the conditions of existing, by compound 1-15 and carboxylic acid R₅' OH and/or acid anhydridesCondensation reaction is carried out, institute is obtained The compound 1-16 stated；

Wherein, R₅' beR₂、R₃、R₄、R₆、R₇、R₈、R₁₀、R₁₅And R₁₇Definition it is same It is upper described.

In the preparation method of the compound 1-16, the condensation reaction can be anti-for such condensation in this field The conventional method answered, particularly preferably following reaction methods and condition in the present invention:

In the preparation method of the compound 1-16, the preferred halogenated hydrocarbon solvent of the organic solvent is described The preferred chlorinated hydrocarbon solvent of halogenated hydrocarbon solvent, the preferred methylene chloride of the chlorinated hydrocarbon solvent.

In the preparation method of the compound 1-16, the volume mass ratio of the organic solvent and compound 1-15 It is preferred that 1mL/g~100mL/g, further preferred 1mL/g~20mL/g.

In the preparation method of the compound 1-16, the carboxylic acid R₅' OH or acid anhydridesWith institute The molar ratio of the compound 1-15 stated preferably 1~3.

In the preparation method of the compound 1-16, preferred 1- ethyl-(the 3- dimethylamino third of the condensing agent Base) carbodiimide hydrochloride (EDCHCl or EDCI, CAS:25952-53-8).

In the preparation method of the compound 1-16, the molar ratio of the condensing agent and the compound 1-15 It is preferred that 1~3.

In the preparation method of the compound 1-16, the preferred 4-dimethylaminopyridine of the catalyst (DMAP, ) or 1- hydroxy benzo triazole (HoBT, CAS:2592-95-2) CAS:1122-58-3.

In the preparation method of the compound 1-16, the molar ratio of the catalyst and the compound 1-15 It is preferred that 0.01~0.1, further preferred 0.01~0.04.

In the preparation method of the compound 1-16, the temperature of the condensation reaction is 10 DEG C~60 DEG C, into one Preferably 15 DEG C~30 DEG C of step.

In the preparation method of the compound 1-16, the process of the condensation reaction can be using in this field Traditional test methods (such as TLC, HPLC or NMR) are monitored, as reaction end when generally being disappeared using compound 1-15, preferably instead 1 hour~24 hours, further preferred 4 hours~10 hours between seasonable.

The preparation method of the compound 1-16 preferably includes following post-processing step: after reaction, adjust pH to 9.0~10.0, extraction, organic phase adds flash column chromatography separation (FLASH pillar layer separation) after methanol eddy after removing solvent, obtains To compound 1-16 after purification.The adjusting pH can use inorganic base, the preferred sodium hydroxide of the inorganic base； The inorganic base can participate in reaction in the form of its aqueous solution, when inorganic base participates in reaction in the form of its aqueous solution, The preferred 3mol/L of the molar concentration of the aqueous solution of the inorganic base, the molar concentration refer to the mole and nothing of inorganic base The ratio of machine aqueous alkali total volume.The extraction can be using the conventional method of extracting operation in this field, the extraction The preferred halogenated hydrocarbon solvent of the solvent of use, the preferred chlorinated hydrocarbon solvent of the halogenated hydrocarbon solvent, the chlorinated hydrocarbon The preferred methylene chloride of solvent.The flash column chromatography separation (FLASH pillar layer separation) can be using such behaviour in this field The conventional method and condition of work, flash column chromatography separate (FLASH pillar layer separation) use silica gel specification preferably 200 mesh~ 400 mesh silica gel.

The preparation method of heretofore described compound 1-17 is preferably straight through single step reaction by the compound 1-15 Connect preparation comprising following steps: in organic solvent, under the conditions of condensing agent is existing, by carboxylic acid R₅OH, acid anhydridesCarboxylic acid R₅' OH and acid anhydridesOne or both of be condensed with compound 1-15 it is anti- It answers, obtains the compound 1-17；

Wherein, R₅ForR₅' beR₂、 R₃、R₄、R₆、R₇、R₈、R₁₀、R₁₅And R₁₇Definition it is same as above.

In the preferred preparation method of the compound 1-17, the preferred halogenated hydrocarbon solvent of the organic solvent, institute The preferred chlorinated hydrocarbon solvent of the halogenated hydrocarbon solvent stated, the preferred methylene chloride of the chlorinated hydrocarbon solvent.

In the preferred preparation method of the compound 1-17, the volume matter of the organic solvent and compound 1-15 Amount is than preferred 1mL/g~100mL/g, further preferred 1mL/g~20mL/g.

In the preferred preparation method of the compound 1-17, the carboxylic acid R₅OH, acid anhydridesCarboxylic Sour R₅' OH and acid anhydridesOne or both of molar ratio preferably 1~6 with the compound 1-15, into One step preferably 2~5.

In the preferred preparation method of the compound 1-17, preferred 1- ethyl-(the 3- dimethylamino of the condensing agent Base propyl) carbodiimide hydrochloride (EDCHCl or EDCI, CAS:25952-53-8).

In the preferred preparation method of the compound 1-17, the condensing agent rubs with the compound 1-15's That ratio preferably 1~6, further preferred 3~5.

In the preferred preparation method of the compound 1-17, the preferred 4-dimethylaminopyridine of the catalyst (DMAP, CAS:1122-58-3) or 1- hydroxy benzo triazole (HoBT, CAS:2592-95-2).

In the preferred preparation method of the compound 1-17, the catalyst rubs with the compound 1-15's That ratio preferably 0.01~0.1, further preferred 0.03~0.07.

In the preferred preparation method of the compound 1-17, the temperature of the condensation reaction is 10 DEG C~60 DEG C, Further preferred 15 DEG C~30 DEG C.

In the preferred preparation method of the compound 1-17, the process of the condensation reaction can use this field In traditional test methods (such as TLC, HPLC or NMR) be monitored, generally using compound 1-16 disappear when as reaction end, it is excellent Select the reaction time 1 hour~24 hours, further preferred 4 hours~10 hours.

The preferred preparation method of the compound 1-17 preferably includes following post-processing step: after reaction, adjusting PH to 9.0~10.0, extraction, organic phase add flash column chromatography separation (FLASH column chromatography point after methanol eddy after removing solvent From), obtain compound 1-18 after purification.The adjusting pH can use inorganic base, the preferred hydrogen of the inorganic base Sodium oxide molybdena；The inorganic base can participate in reaction in the form of its aqueous solution, when inorganic base is participated in the form of its aqueous solution When reaction, the preferred 3mol/L of the molar concentration of the aqueous solution of the inorganic base, the molar concentration refers to rubbing for inorganic base The ratio of your amount and inorganic base aqueous solution total volume.The extraction can be using the conventional method of extracting operation in this field, institute The preferred halogenated hydrocarbon solvent of solvent that the extraction stated uses, the preferred chlorinated hydrocarbon solvent of the halogenated hydrocarbon solvent are described The preferred methylene chloride of chlorinated hydrocarbon solvent.The flash column chromatography separation (FLASH pillar layer separation) can use this field In the generic operation conventional method and condition, flash column chromatography separate (FLASH pillar layer separation) use silica gel specification it is excellent Select 200 mesh~400 mesh silica gel.

In the preparation method of the compound 1-18, following steps are preferably included: by compound 1-14 and chemical combination ObjectCondensation reaction is carried out, the compound 1-15 is obtained；

Wherein, R₂、R₃、R₄、R₆、R₇、R₁₀And R₁₅Definition it is same as above.

In the preparation method of the compound 1-15, the condensation reaction can be anti-for such condensation in this field The conventional method answered, particularly preferably following reaction methods and condition in the present invention:

In the preparation method of the compound 1-15, the condensation reaction can in a solvent or solvent-free item It is carried out under part, when the condensation reaction carries out in a solvent, the preferred alcohols solvent of the solvent, the alcohols solvent It is preferred that methanol and/or ethyl alcohol.When the condensation reaction carries out in a solvent, the solvent and the compound 1-14 Volume mass than preferred 1mL/g~100mL/g, further preferred 1mL/g~20mL/g.

In the preparation method of the compound 1-15, the compoundWith the compound 1-14 molar ratio preferably 1~6, further preferred 1~3.

In the preparation method of the compound 1-15, preferably 40 DEG C~100 DEG C of the temperature of the condensation reaction, into Preferably 40 DEG C~70 DEG C of one step.

In the preparation method of the compound 1-15, the process of the condensation reaction can be using in this field Traditional test methods (such as TLC, HPLC or NMR) are monitored, as reaction end when generally being disappeared using compound 1-14, preferably instead 1 hour~24 hours, further preferred 3 hours~10 hours between seasonable.

The preparation method of the compound 1-15 preferably carries out under the conditions of acid catalyzed, and the acid is preferably organic Acid, the preferred acetic acid of the organic acid；The molar ratio preferably 1~6 of the acid and the compound 1-14, it is further excellent Select 1~3.

Following post-processing step is preferably included in the preparation method of the compound 1-15, after reaction, is removed molten Agent, flash column chromatography separation, just obtains compound 1-15 after purification.The removing solvent can be using such in this field The conventional method of operation carries out, and preferably carries out at reduced pressure.Flash column chromatography separation (the FLASH column chromatography point From) can be adopted using the conventional method and condition of the generic operation in this field, flash column chromatography separation (FLASH pillar layer separation) The specification of silica gel preferably 200 mesh~400 mesh silica gel.

In the preparation method of the compound 1-18, preferably include following steps: by compound 1 ' -6 and acid into Row hydrolysis obtains the compound 1-14；

Wherein, R₂、R₃、R₄、R₆And R₇Definition it is same as above.

In the preparation method of the compound 1-14, the hydrolysis can be anti-for such hydrolysis in this field The conventional method answered, particularly preferably following reaction methods and condition in the present invention:

In the preparation method of the compound 1-14, the hydrolysis can in a solvent or solvent-free item It is carried out under part, when the hydrolysis carries out in a solvent, the preferred alcohols solvent of the solvent, the alcohols solvent Preferred alcohol.When the hydrolysis carries out in a solvent, the volume matter of the solvent and the compound 1 ' -6 Amount is than preferred 1mL/g~20mL/g, further preferred 1mL/g~5mL/g.

In the preparation method of the compound 1-14, the preferred inorganic acid of acid；The preferred salt of the inorganic acid Acid；The inorganic acid can participate in reaction in the form of its solution；In the solution of the inorganic acid solvent can for water and/ Or alcohol, the preferred methanol of the alcohol and/or ethyl alcohol；Preferred 1mol/L~the 3mol/L of the molar concentration of the inorganic acid solution； The molar concentration refers to the ratio of the mole of inorganic acid and the liquor capacity of inorganic acid.

In the preparation method of the compound 1-14, the acid is excellent with the molar ratio of the compound 1 ' -6 Select 1~10, further preferred 3~6.

In the preparation method of the compound 1-14, preferably 10 DEG C~60 DEG C of the temperature of the hydrolysis, into Preferably 15 DEG C~30 DEG C of one step.

In the preparation method of the compound 1-14, the process of the hydrolysis can be using in this field Traditional test methods (such as TLC, HPLC or NMR) are monitored, as reaction end when generally being disappeared using compound 1 ' -6, preferably instead 1 hour~24 hours, further preferred 2 hours~6 hours between seasonable.

The preparation method of the compound 1-14 preferably includes following post-processing step, after reaction, adjust pH to 9.0~10.0, extraction is concentrated to get compound I-14 after purification.The adjusting pH can use inorganic base, described The preferred sodium hydroxide of inorganic base；The inorganic base can participate in reaction in the form of its aqueous solution, when inorganic base is with its water When the form of solution participates in reaction, the preferred 3mol/L of the molar concentration of the aqueous solution of the inorganic base, the molar concentration Refer to the molal quantity of inorganic base and the ratio of inorganic base aqueous solution total volume.The extraction can be grasped using extracting in this field The conventional method of work, the preferred halogenated hydrocarbon solvent of solvent that the extraction uses, the preferred chloro of the halogenated hydrocarbon solvent Hydrocarbon solvent, the preferred methylene chloride of the chlorinated hydrocarbon solvent.

In the preparation method of the compound 1-14, following steps are preferably included: in organic solvent, by chemical combination Object 1 ' -7 and hydrazine acetate carry out condensation reaction, obtain the compound 1 ' -6；

Wherein, R₂、R₃、R₄、R₆、R₇And R₁₄Definition it is same as above.

In the preparation method of the compound 1 ' -6, the condensation reaction can be anti-for such condensation in this field The conventional method answered, particularly preferably following reaction methods and condition in the present invention:

In the preparation method of the compound 1 ' -6, the preferred alcohols solvent of the organic solvent, the alcohols The preferred methanol of solvent and/or ethyl alcohol.

In the preparation method of the compound 1 ' -6, the volume of the organic solvent and the compound 1 ' -7 Mass ratio preferred 1mL/g~100mL/g, further preferred 1mL/g~10mL/g.

In the preparation method of the compound 1 ' -6, the molar ratio of the compound 1 ' -7 and the hydrazine acetate Value preferably 1~5, further preferred 3~4.

In the preparation method of the compound 1 ' -6, preferably 40 DEG C~100 DEG C of the temperature of the condensation reaction, into Preferably 50 DEG C~80 DEG C of one step.

In the preparation method of the compound 1 ' -6, the process of the condensation reaction can be using in this field Traditional test methods (such as TLC, HPLC or NMR) are monitored, as reaction end when generally being disappeared using compound 1 ' -7, preferably instead 1 hour~72 hours, further preferred 24 hours~48 hours between seasonable.

The preparation method of the compound 1 ' -6 preferably includes following post-processing step, after reaction, adjust pH to 9.0~10.0, extraction is concentrated to get compound I ' -6.The adjusting pH can use inorganic base, the inorganic base It is preferred that sodium hydroxide；The inorganic base can participate in reaction in the form of its aqueous solution, when inorganic base is with the shape of its aqueous solution When formula participates in reaction, the preferred 3mol/L of the molar concentration of the aqueous solution of the inorganic base, the molar concentration refers to inorganic The molal quantity of alkali and the ratio of inorganic base aqueous solution total volume.The extraction can be using the routine of extracting operation in this field Method, the preferred halogenated hydrocarbon solvent of solvent that the extraction uses, the preferred chlorinated hydrocarbon solvent of the halogenated hydrocarbon solvent, The preferred methylene chloride of the chlorinated hydrocarbon solvent.

In the preparation method of the compound 1 ' -6, the hydrazine acetate be commercially available can also use it is following Method preparation: acetic acid is added drop-wise in hydrazine hydrate, is carried out condensation reaction, is obtained hydrazine acetate.

The preparation method of the hydrazine acetate can be using the conventional method and condition of the condensation reaction in this field, this hair There are particularly preferred following reaction method and condition in bright:

In the preparation method of the hydrazine acetate, the molar ratio preferably 1 of the hydrazine hydrate and the acetic acid~ 2；Hydrazine hydrate described in the hydrazine hydrate can be hydrated hydrazine reagent using the conventional commercial in this field, the hydrazine hydrate Mass percentage preferably 20%~90%, the mass percentage refer to that the quality of hydrazine accounts for the percentage of hydrazine hydrate gross mass Than.

In the preparation method of the hydrazine acetate, the dropping temperature preferably 0 of " acetic acid is added drop-wise in hydrazine hydrate " ~10 DEG C.

In the preparation method of the hydrazine acetate, preferably 10 DEG C~50 DEG C of the temperature of the condensation reaction, further It is preferred that 15 DEG C~30 DEG C.

In the preparation method of the hydrazine acetate, the time of the condensation reaction preferably 0.1 hour~5 hours, into One step preferably 0.5 hour~1 hour.

In the present invention, the further preferably following route of the preparation method method of the macrolides compound 1:

The present invention also provides the preparation methods of the macrolides compound 1 ', work as R₁ForWhen, it is excellent Choosing method 1 '；Work as R₁ForWhen, it is preferred to use method 2 '；Work as R₁ForWhen can use method 1 ' or method 2 '.

Method 1 ': in a solvent, compound 1 ' -2 is subjected to alcoholysis reaction, obtains compound 1 ' -1；

In the method for prepare compound 1 ' -1, the alcoholysis reaction can be the normal of such alcoholysis reaction in this field Rule method, particularly preferably following reaction methods and condition in the present invention:

In the method for prepare compound 1 ' -1, the preferred alcohols solvent of the solvent, the preferred first of the alcohols solvent Alcohol and/or ethyl alcohol.

In the method for prepare compound 1 ' -1, the volume mass of the solvent and the compound 1 ' -2 is than preferred 1mL/g~100mL/g, further preferred 1mL/g~20mL/g.

It is preferably 40 DEG C~100 DEG C of the temperature of the alcoholysis reaction, further excellent in the method for prepare compound 1 ' -1 Select 50 DEG C~80 DEG C.

In the method for prepare compound 1 ' -1, the process of the alcoholysis reaction can be using the conventional survey in this field Method for testing (such as TLC, HPLC or NMR) is monitored, as reaction end when generally being disappeared using compound 1 ' -2, preferred reaction time 1 hour~24 hours, further preferred 1 hour~5 hours.

The method of prepare compound 1 ' -1 preferably includes following post-processing step；After reaction, column chromatography purifies to obtain Crude product, obtain compound 1 ' -1.The condition of the column chromatography purifying can be using the generic operation in this field Conventional method, can be using the mixed solvent of alcohols solvent and halogenated hydrocarbon solvent as eluant, eluent, the preferred first of the alcohols solvent Alcohol and/or ethyl alcohol；The preferred chlorinated hydrocarbon solvent of the halogenated hydrocarbon solvent, the preferred dichloromethane of the chlorinated hydrocarbon solvent Alkane；The in the mixed solvent alcohols solvent of the alcohols solvent and halogenated hydrocarbon solvent and the volume ratio of halogenated hydrocarbon solvent are preferred 1:20~20:1.

In the preparation method of the compound 1 ' -1, following steps are preferably included: in organic solvent, aoxidizing Under the conditions of agent and catalyst are existing, the progress of compound 1 ' -3 oxidation reaction is obtained into the compound 1 ' -2, it is described Oxidant be dimethyl sulfoxide and 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride (EDCHCl or EDCI, CAS:25952-53-8).

Wherein, R₂、R₃、R₄、R₆、R₇And R₁₄Definition it is same as above；

In the preparation method of the compound 1 ' -2, the oxidation reaction can be anti-for such oxidation in this field The conventional method answered, particularly preferably following reaction methods and condition in the present invention:

In the preparation method of the compound 1 ' -2, the preferred halogenated hydrocarbon solvent of the organic solvent；Described The preferred chlorinated hydrocarbon solvent of halogenated hydrocarbon solvent；The preferred methylene chloride of the chlorinated hydrocarbon solvent.

In the preparation method of the compound 1 ' -2, the volume of the organic solvent and the compound 1 ' -3 Mass ratio preferred 1mL/g~20mL/g, further preferred 3mL/g~8mL/g.

In the preparation method of the compound 1 ' -2, the dimethyl sulfoxide rubs with the compound 1 ' -3 That ratio preferably 1~20, further preferred 1~5.

In the preparation method of the compound 1 ' -2, the dimethyl sulfoxide and 1- ethyl-(the 3- diformazan Base aminopropyl) carbodiimide hydrochloride (EDCHCl, CAS:25952-53-8) molar ratio preferably 1~4, further it is excellent Select 2~3.

In the preparation method of the compound 1 ' -2, the preferred pyridine hydrochloride of the catalyst (Py ﹒ HCl；CAS: 628-13-7) and/or pyridinium trifluoroacetate (TFA ﹒ Py；CAS:464-05-1).

In the preparation method of the compound 1 ' -2, the molar ratio of the dimethyl sulfoxide and the catalyst Value preferably 1~4, further preferred 2~3.

In the preparation method of the compound 1 ' -2, the temperature of the oxidation reaction is 10 DEG C~60 DEG C, into one Preferably 15 DEG C~30 DEG C of step.

In the preparation method of the compound 1 ' -2, the process of the oxidation reaction can be using in this field Traditional test methods (such as TLC, HPLC or NMR) are monitored, as reaction end when generally being disappeared using compound 1 ' -3, preferably instead 1 hour~48 hours, further preferred 15 hours~30 hours between seasonable.

In the preparation method of the compound 1 ' -2, the oxidation reaction preferably includes following steps: compound I ' -3 and pyridine hydrochloride are added to dimethyl sulfoxide and 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride In the solution that (EDCHCl, CAS:25952-53-8) and organic solvent are formed, carries out oxidation reaction and obtain compound 1 ' -2.

In the preparation method of the compound 1 ' -2, the oxidation reaction preferably includes following post-processing step: After reaction, add water, liquid separation, water phase is extracted with organic solvent, merges organic phase, and concentration obtains compound 1 '-after purification 2。

In the preparation method of the compound 1 ' -1, preferably include following steps: by compound 1 ' -4 and acid into Row hydrolysis obtains the compound 1 ' -3；

In the preparation method of the compound 1 ' -3, the hydrolysis can be anti-for such hydrolysis in this field The conventional method answered, particularly preferably following reaction methods and condition in the present invention:

In the preparation method of the compound 1 ' -3, the hydrolysis can in a solvent or solvent-free item It is carried out under part, when the hydrolysis carries out in a solvent, the preferred alcohols solvent of the solvent, the alcohols solvent It is preferred that methanol and/or ethyl alcohol.When the hydrolysis carries out in a solvent, the solvent and the compound 1 ' -4 Volume mass than preferred 0.1mL/g~10mL/g, further preferred 0.1mL/g~2mL/g.

In the preparation method of the compound 1 ' -3, the preferred inorganic acid of acid；The preferred salt of the inorganic acid Acid；The inorganic acid can participate in reaction in the form of its solution；In the solution of the inorganic acid solvent can for water and/ Or alcohol, the preferred methanol of the alcohol and/or ethyl alcohol；Preferred 1mol/L~the 3mol/L of the molar concentration of the inorganic acid solution.

In the preparation method of the compound 1 ' -3, the acid is preferred with the molar ratio of the compound 1 ' -4 1~10, further preferred 2~5.

In the preparation method of the compound 1 ' -3, preferably 10 DEG C~60 DEG C of the temperature of the hydrolysis, into Preferably 15 DEG C~30 DEG C of one step.

In the preparation method of the compound 1 ' -3, the process of the hydrolysis can be using in this field Traditional test methods (such as TLC, HPLC or NMR) are monitored, as reaction end when generally being disappeared using compound 1 ' -4, preferably instead 1 hour~24 hours, further preferred 3 hours~8 hours between seasonable.

The preparation method of the compound 1 ' -3 preferably includes following post-processing step, after reaction, adjust pH to 9.0~10.0 (preferably pH9.7), extraction, are concentrated to get compound I ' -3.The adjusting pH can use inorganic base, The preferred sodium hydroxide of the inorganic base；The inorganic base can be participated in the form of its aqueous solution reaction, when inorganic base with When the form of its aqueous solution participates in reaction, the preferred 3mol/L of the molar concentration of the aqueous solution of the inorganic base, mole Concentration refers to the mole of inorganic base and the ratio of inorganic base aqueous solution total volume.The extraction can be used and be extracted in this field The conventional method of operation, the preferred halogenated hydrocarbon solvent of solvent that the extraction uses, the preferred chlorine of the halogenated hydrocarbon solvent For hydrocarbon solvent, the preferred methylene chloride of the chlorinated hydrocarbon solvent.

In the preparation method of the compound 1 ' -1, following steps are preferably included: in organic solvent, by chemical combination Object 1 ' -5 and acetic anhydride carry out condensation reaction, obtain the compound 1 ' -4；

In the preparation method of the compound 1 ' -4, the condensation reaction can be anti-for such condensation in this field The conventional method answered, particularly preferably following reaction methods and condition in the present invention:

In the preparation method of the compound 1 ' -4, the preferred halogenated hydrocarbon solvent of the organic solvent is described The preferred chlorinated hydrocarbon solvent of halogenated hydrocarbon solvent, the preferred methylene chloride of the chlorinated hydrocarbon solvent.

In the preparation method of the compound 1 ' -4, the volume mass ratio of the organic solvent and compound 1 ' -5 It is preferred that 1mL/g~10mL/g, further preferred 2mL/g~5mL/g.

In the preparation method of the compound 1 ' -4, the molar ratio preferably 1 of the acetic anhydride and compound 1 ' -5 ~10, further preferred 1~5.

In the preparation method of the compound 1 ' -4, preferably 10 DEG C~60 DEG C of the temperature of the condensation reaction, into Preferably 15 DEG C~30 DEG C of one step.

In the preparation method of the compound 1 ' -4, the process of the condensation reaction can be using in this field Traditional test methods (such as TLC, HPLC or NMR) are monitored, as reaction end when generally being disappeared using compound 1 ' -5, preferably instead 1 hour~24 hours, further preferred 1 hour~5 hours between seasonable.

The preparation method of the compound 1 ' -4 preferably includes following post-processing step, after reaction, adjust pH to 9.0~10.0 (preferably pH9.7), extraction, are concentrated to get compound I ' -3.The adjusting pH can use inorganic base, The preferred sodium hydroxide of the inorganic base；The inorganic base can be participated in the form of its aqueous solution reaction, when inorganic base with When the form of its aqueous solution participates in reaction, the preferred 3mol/L of the molar concentration of the aqueous solution of the inorganic base, mole Concentration refers to the mole of inorganic base and the ratio of inorganic base aqueous solution total volume.The extraction can be used and be extracted in this field The conventional method of operation, the preferred halogenated hydrocarbon solvent of solvent that the extraction uses, the preferred chlorine of the halogenated hydrocarbon solvent For hydrocarbon solvent, the preferred methylene chloride of the chlorinated hydrocarbon solvent.

In the preparation method of the compound 1 ' -1, following steps are preferably included: in organic solvent, condensing agent Under the conditions of existing, compound 1 ' -6 and carboxylic acid 2 are subjected to condensation reaction, obtain the compound 1 ' -5；

In the preparation method of the compound 1 ' -5, the condensation reaction can be anti-for such condensation in this field The conventional method answered, particularly preferably following reaction methods and condition in the present invention:

In the preparation method of the compound 1 ' -5, the preferred halogenated hydrocarbon solvent of the organic solvent is described The preferred chlorinated hydrocarbon solvent of halogenated hydrocarbon solvent, the preferred methylene chloride of the chlorinated hydrocarbon solvent.

In the preparation method of the compound 1 ' -5, the volume mass ratio of the organic solvent and compound 1 ' -6 It is preferred that 1mL/g~100mL/g, further preferred 1mL/g~10mL/g.

In the preparation method of the compound 1 ' -5, preferred 1- ethyl-(the 3- dimethylamino third of the condensing agent Base) carbodiimide hydrochloride (EDCHCl, CAS:25952-53-8) and/or dicyclohexylcarbodiimide (DCC, CAS:538- 75-0)。

In the preparation method of the compound 1 ' -5, the molar ratio of the condensing agent and the compound 1 ' -6 Value preferably 1~5, further preferred 1~2.

In the preparation method of the compound 1 ' -5, preferably 10 DEG C~60 DEG C of the temperature of the condensation reaction, into Preferably 15 DEG C~30 DEG C of one step.

In the preparation method of the compound 1 ' -5, the process of the condensation reaction can be using in this field Traditional test methods (such as TLC, HPLC or NMR) are monitored, as reaction end when generally being disappeared using compound 1 ' -6, preferably instead 1 hour~24 hours between seasonable.

The preparation method of the compound 1 ' -5 preferably includes following post-processing step, after reaction, adjust pH to 9.0~10.0 (preferably pH9.7), extraction, are concentrated to get compound I ' -5.The adjusting pH can use inorganic base, The preferred sodium hydroxide of the inorganic base；The inorganic base can be participated in the form of its aqueous solution reaction, when inorganic base with When the form of its aqueous solution participates in reaction, the preferred 3mol/L of the molar concentration of the aqueous solution of the inorganic base, mole Concentration refers to the mole of inorganic base and the ratio of inorganic base aqueous solution total volume.The extraction can be used and be extracted in this field The conventional method of operation, the preferred halogenated hydrocarbon solvent of solvent that the extraction uses, the preferred chlorine of the halogenated hydrocarbon solvent For hydrocarbon solvent, the preferred methylene chloride of the chlorinated hydrocarbon solvent.

In the preparation method of the compound 1 ' -1, following steps are preferably included: in organic solvent, by chemical combination Object 1 ' -7 and hydrazine acetate carry out condensation reaction, obtain the compound 1 ' -6；

Wherein, R₂、R₃、R₄、R₆And R₇Definition it is same as above.The preparation method of the compound 1 ' -6 is same as above institute It states.

In the present invention, in the preparation method of the macrolides compound 1 ', method 1 ' further preferably use with Lower route:

Method 2 ': willOne or both of with compound 1 ' -12 into Row condensation reaction obtains compound 1 ' -13；

In the preparation method of compound 1 ' -13, the condensation reaction can be such condensation reaction in this field Conventional method, particularly preferably following reaction methods and condition in the present invention:

The preparation method of the compound 1 ' -13 can carry out, in a solvent or under the conditions of solvent-free when described When the preparation method of compound 1 ' -13 carries out in a solvent, the preferred alcohols solvent of the solvent and/or halogenated hydrocarbon solvent, The preferred methanol of the alcohols solvent and/or ethyl alcohol；The preferred chlorinated hydrocarbon solvent of the halogenated hydrocarbon solvent, the chloro The preferred methylene chloride of hydrocarbon solvent.When the preparation method of the compound 1 ' -13 carries out in a solvent, the solvent with The volume mass of the compound 1 ' -12 is than preferred 1mL/g~100mL/g, further preferred 1mL/g~50mL/g.

It is described in the preparation method of the compound 1 ' -13 One or both of molar ratio preferably 0.5~10 with the compound 1 ' -12.

In the preparation method of the compound 1 ' -13, preferably 30 DEG C~100 DEG C of the temperature of the condensation reaction, Further preferred 40 DEG C~80 DEG C.

In the preparation method of the compound 1 ' -13, the process of the condensation reaction can be using in this field Traditional test methods (such as TLC, HPLC or NMR) be monitored, generally using compound 1 ' -12 disappear when as reaction end, it is excellent Select the reaction time 1 hour~48 hours, further preferred 1 hour~30 hours.

In the preparation method of the compound 1 ' -13, work as useFor reaction raw materials When, the condensation reaction preferably existing for the condensing agent under the conditions of carry out, preferred 1- ethyl-(the 3- diformazan of the condensing agent Base aminopropyl) carbodiimide hydrochloride (EDCHCl, CAS:25952-53-8) and/or dicyclohexylcarbodiimide (DCC, CAS:538-75-0)；The molar ratio preferably 1~10, further preferred 4 of the condensing agent and the compound 1 ' -12~ 6。

In the preparation method of the compound 1 ' -13, following steps are preferably included: in organic solvent, will change It closes object 1 ' -11 and hydrazine hydrate carries out reduction reaction and obtains the compound 1 ' -12；

Wherein, R₂、R₃、R₄、R₆And R₇Definition it is same as above.R₁₈With R₁₉Independent is C₁~C₄Alkyl (example Such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tert-butyl, preferably methyl) or R₁₈、R₁₉And the carbon of their connections Be collectively formed 3-6 membered cyclic structure (such asIt is preferred that

In the preparation method of the compound 1 ' -12, the reduction reaction can be such reduction in this field The conventional method of reaction, particularly preferably following reaction methods and condition in the present invention:

In the preparation method of the compound 1 ' -12, the preferred alcohols solvent of the organic solvent, the alcohols The preferred methanol of solvent and/or ethyl alcohol.

In the preparation method of the compound 1 ' -12, the body of the organic solvent and the compound 1 ' -11 The product preferred 1mL/g~100mL/g of mass ratio, further preferred 1mL/g~10mL/g.

In the preparation method of the compound 1 ' -12, mole of the hydrazine hydrate and the compound 1 ' -12 Ratio preferably 1~3.The hydrazine hydrate can be hydrated hydrazine reagent using the conventional commercial in this field, the hydrazine hydrate Mass percentage preferably 20%~90%, the mass percentage refer to that the quality of hydrazine accounts for the percentage of hydrazine hydrate gross mass Than.

In the preparation method of the compound 1 ' -12, preferably 30 DEG C~100 DEG C of the temperature of the reduction reaction, Further preferred 50 DEG C~90 DEG C.

In the preparation method of the compound 1 ' -12, the process of the reduction reaction can be using in this field Traditional test methods (such as TLC, HPLC or NMR) be monitored, generally using compound 1 ' -11 disappear when as reaction end, it is excellent Select the reaction time 1 hour~10 hours, further preferred 3 hours~6 hours.

The preparation method of the compound 1 ' -12, preferably includes following post-processing step: after reaction, extraction is dense Contracting, obtains compound 1 ' -12 after purification.

In the preparation method of the compound 1 ' -13, following steps are preferably included: in organic solvent, in oxygen Under the conditions of agent and catalyst are existing, the progress of compound 1 ' -10 oxidation reaction is obtained into the compound 1 ' -11, The oxidant be dimethyl sulfoxide and 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride (EDCHCl, CAS:25952-53-8)；

Wherein, R₂、R₃、R₄、R₆、R₇、R₁₈And R₁₉Definition it is same as above；

In the preparation method of the compound 1 ' -11, the oxidation reaction can be such oxidation in this field The conventional method of reaction, particularly preferably following reaction methods and condition in the present invention:

In the preparation method of the compound 1 ' -11, the preferred halogenated hydrocarbon solvent of the organic solvent；Described The preferred chlorinated hydrocarbon solvent of halogenated hydrocarbon solvent；The preferred methylene chloride of the chlorinated hydrocarbon solvent.

In the preparation method of the compound 1 ' -11, the body of the organic solvent and the compound 1 ' -10 The product preferred 1mL/g~100mL/g of mass ratio, further preferred 1mL/g~20mL/g.

In the preparation method of the compound 1 ' -11, the dimethyl sulfoxide and the compound 1 ' -10 Molar ratio preferably 1~20, further preferred 1~5.

In the preparation method of the compound 1 ' -11, the dimethyl sulfoxide and the 1- ethyl-(3- bis- Dimethylaminopropyl) carbodiimide hydrochloride (EDCHCl, CAS:25952-53-8) molar ratio preferably 1~4, further It is preferred that 2~3.

In the preparation method of the compound 1 ' -11, the preferred pyridine hydrochloride of the catalyst (Py ﹒ HCl； ) and/or pyridinium trifluoroacetate (TFA ﹒ Py CAS:628-13-7；CAS:464-05-1).

In the preparation method of the compound 1 ' -11, mole of the dimethyl sulfoxide and the catalyst Ratio preferably 1~20, further preferred 1~5.

In the preparation method of the compound 1 ' -11, the temperature of the oxidation reaction is -10 DEG C~60 DEG C, into Preferably -5 DEG C~30 DEG C of one step.

In the preparation method of the compound 1 ' -11, the process of the oxidation reaction can be using in this field Traditional test methods (such as TLC, HPLC or NMR) be monitored, generally using compound 1 ' -10 disappear when as reaction end, it is excellent Select the reaction time 1 hour~21 hours, further preferred 1 hour~5 hours.

In the preparation method of the compound 1 ' -11, the oxidation reaction preferably includes following steps: by pyridine Dimethyl sulfoxide, compound I ' -10 and 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride is added portionwise in hydrochloride In the solution that salt (EDCHCl, CAS:25952-53-8) and organic solvent are formed, carries out oxidation reaction and obtain compound 1 '- 11。

In the preparation method of the compound 1 ' -11, the oxidation reaction preferably includes following post-processing step: After reaction, pH to 9.0~10.0 is adjusted, extraction is concentrated to get compound I ' -11.The adjusting pH can be adopted With inorganic base, the preferred sodium hydroxide of the inorganic base；The inorganic base can participate in reaction in the form of its aqueous solution, when When inorganic base participates in reaction in the form of its aqueous solution, the preferred 3mol/L of the molar concentration of the aqueous solution of the inorganic base, institute The molar concentration stated refers to the mole of inorganic base and the ratio of inorganic base aqueous solution total volume.The extraction can use ability The conventional method of extracting operation in domain, the preferred halogenated hydrocarbon solvent of solvent that the extraction uses, the halogenated hydrocarbon are molten The preferred chlorinated hydrocarbon solvent of agent, the preferred methylene chloride of the chlorinated hydrocarbon solvent.

In the preparation method of the compound 1 ' -13, preferably include following steps: by compound 1 ' -9 and acid into Row hydrolysis obtains the compound 1 ' -10；

Wherein, R₂、R₃、R₄、R₆、R₇、R₁₈And R₁₉Definition it is same as above.

In the preparation method of the compound 1 ' -10, the hydrolysis can be such hydrolysis in this field The conventional method of reaction, particularly preferably following reaction methods and condition in the present invention:

In the preparation method of the compound 1 ' -10, the hydrolysis can be in a solvent or solvent-free Under the conditions of carry out, when the hydrolysis carries out in a solvent, the preferred alcohols solvent of the solvent, the alcohols is molten The preferred methanol of agent and/or ethyl alcohol.When the hydrolysis carries out in a solvent, the solvent and the compound 1 ' -9 volume mass is than preferred 0.1mL/g~10mL/g, further preferred 0.1mL/g~2mL/g.

In the preparation method of the compound 1 ' -10, the preferred inorganic acid of acid；The preferred salt of the inorganic acid Acid；The inorganic acid can participate in reaction in the form of its solution；In the solution of the inorganic acid solvent can for water and/ Or alcohol, the preferred methanol of the alcohol and/or ethyl alcohol；The mass concentration of the inorganic acid solution preferably 1%~37%；Described Mass percentage concentration refers to that the quality of inorganic acid accounts for the percentage of the gross mass of the solution of inorganic acid.

In the preparation method of the compound 1 ' -10, the acid is excellent with the molar ratio of the compound 1 ' -9 Select 1~20, further preferred 2~5.

In the preparation method of the compound 1 ' -10, preferably 10 DEG C~60 DEG C of the temperature of the hydrolysis, into Preferably 15 DEG C~30 DEG C of one step.

In the preparation method of the compound 1 ' -10, the process of the hydrolysis can be using in this field Traditional test methods (such as TLC, HPLC or NMR) be monitored, generally using compound 1 ' -9 disappear when as reaction end, preferably Reaction time 1 hour~24 hours, further preferred 1 hour~5 hours.

The preparation method of the compound 1 ' -10 preferably includes following post-processing step, after reaction, adjust pH to 9.0~10.0, extraction is concentrated to get compound I ' -10.The adjusting pH can use inorganic base, and described is inorganic The preferred sodium hydroxide of alkali；The inorganic base can participate in reaction in the form of its aqueous solution, when inorganic base is with its aqueous solution When form participates in reaction, the preferred 3mol/L of the molar concentration of the aqueous solution of the inorganic base, the molar concentration refers to nothing The mole of machine alkali and the ratio of inorganic base aqueous solution total volume.The extraction can be using the routine of extracting operation in this field Method, the preferred halogenated hydrocarbon solvent of solvent that the extraction uses, the preferred chlorinated hydrocarbon solvent of the halogenated hydrocarbon solvent, The preferred methylene chloride of the chlorinated hydrocarbon solvent.

In the preparation method of the compound 1 ' -13, following steps are preferably included: in organic solvent, will change It closes object 1 ' -8 and acetic anhydride carries out condensation reaction, obtain the compound 1 ' -9；

In the preparation method of the compound 1 ' -9, the condensation reaction can be anti-for such condensation in this field The conventional method answered, particularly preferably following reaction methods and condition in the present invention:

In the preparation method of the compound 1 ' -9, the preferred halogenated hydrocarbon solvent of the organic solvent is described The preferred chlorinated hydrocarbon solvent of halogenated hydrocarbon solvent, the preferred methylene chloride of the chlorinated hydrocarbon solvent.

In the preparation method of the compound 1 ' -9, the volume mass ratio of the organic solvent and compound 1 ' -8 It is preferred that 1mL/g~100mL/g, further preferred 1mL/g~10mL/g.

In the preparation method of the compound 1 ' -9, the molar ratio preferably 1 of the acetic anhydride and compound 1 ' -8 ~20, further preferred 1~5.

In the preparation method of the compound 1 ' -9, preferably 10 DEG C~60 DEG C of the temperature of the condensation reaction, into Preferably 15 DEG C~30 DEG C of one step.

In the preparation method of the compound 1 ' -9, the process of the condensation reaction can be using in this field Traditional test methods (such as TLC, HPLC or NMR) are monitored, as reaction end when generally being disappeared using compound 1 ' -8, preferably instead 1 hour~24 hours, further preferred 2 hours~6 hours between seasonable.

The preparation method of the compound 1 ' -9 preferably includes following post-processing step, after reaction, adjust pH to 9.0~10.0, extraction is concentrated to get compound I ' -3.The adjusting pH can use inorganic base, the inorganic base It is preferred that sodium hydroxide；The inorganic base can participate in reaction in the form of its aqueous solution, when inorganic base is with the shape of its aqueous solution When formula participates in reaction, the preferred 3mol/L of the molar concentration of the aqueous solution of the inorganic base, the molar concentration refers to inorganic The mole of alkali and the ratio of inorganic base aqueous solution total volume.The extraction can be using the routine of extracting operation in this field Method, the preferred halogenated hydrocarbon solvent of solvent that the extraction uses, the preferred chlorinated hydrocarbon solvent of the halogenated hydrocarbon solvent, The preferred methylene chloride of the chlorinated hydrocarbon solvent.

In the preparation method of the compound 1 ' -13, following steps are preferably included: by compound 1 ' -6 and chemical combination ObjectCondensation reaction is carried out, the compound 1 ' -8 is obtained；

In the preparation method of the compound 1 ' -8, the condensation reaction can be anti-for such condensation in this field The conventional method answered, particularly preferably following reaction methods and condition in the present invention:

In the preparation method of the compound 1 ' -8, the condensation reaction can in a solvent or solvent-free item It is carried out under part, when the condensation reaction carries out in a solvent, the preferred alcohols of the solvent and/or halogenated hydrocarbon solvent, institute The preferred methanol of the alcohols solvent stated, the preferred methylene chloride of the halogenated hydrocarbon solvent.When the condensation reaction in a solvent When progress, the volume mass of the solvent and the compound 1 ' -6 is than preferred 1mL/g~10mL/g, further preferably 1mL/g~5mL/g.

In the preparation method of the compound 1 ' -8, the compound 1 ' -6 and the compoundMolar ratio preferably 1~10, further preferred 1~5.

In the preparation method of the compound 1 ' -8, preferably 40 DEG C~100 DEG C of the temperature of the condensation reaction, into Preferably 40 DEG C~70 DEG C of one step.

In the preparation method of the compound 1 ' -8, the process of the condensation reaction can be using in this field Traditional test methods (such as TLC, HPLC or NMR) are monitored, as reaction end when generally being disappeared using compound 1 ' -6, preferably instead 1 hour~24 hours, further preferred 2 hours~6 hours between seasonable.

Following post-processing step is preferably included in the preparation method of the compound 1 ' -8, after reaction, is removed molten Agent just obtains the compound 1 ' -8.The removing solvent can using the generic operation in this field conventional method into Row, preferably carries out at reduced pressure.

In the preparation method of the compound 1 ' -13, following steps are preferably included: in organic solvent, will change It closes object 1 ' -7 and hydrazine acetate carries out condensation reaction, obtain the compound 1 ' -6；

Each condition of the preparation method of the compound 1 ' -6 is same as above.

In the present invention, in the preparation method of the macrolides compound 1 ', method 2 ' further preferably use with Lower route:

The present invention also provides compound 1 ' -2, compound 1 ' -3, compound 1 ' -4, compound 1 ' -5, compound 1 ' -6, Compound 1 ' -7, compound 1 ' -8, compound 1 ' -9, compound 1 ' -10, compound 1 ' -11, compound 1 ' -12, compound 1- 14, compound 1-15, compound 1-16 or compound 1-17, structure are as follows:

Wherein, R₂、R₃、R₄、R₆、R₇、R₁₀、R₁₅、R₁₇、R₅、R₅’、R₁₈And R₁₉Definition it is same as above.

Heretofore described macrolides compound 1 or 1 ' salt refer to macrolides compound 1 of the invention Or 1 ' with acid react formation salt, the acid can be inorganic acid conventional in the art or organic acid.

The present invention also provides the macrolides compounds 1, macrolides compound 1 ', described The salt of the salt of macrolides compound 1 or the macrolides compound 1 ' is in preparation synergy beta-lactam antibiotic To the application in the drug of the inhibiting effect of methicillin-resistant staphylococcus aureus.

The present invention also provides a kind of pharmaceutical compositions comprising the macrolides compound 1, the big ring In the salt of lactone compound 1 ', the salt of the macrolides compound 1 and the macrolides compound 1 ' One or more and beta-lactam antibiotic.

In pharmaceutical composition of the present invention, the macrolides compound as shown in Equation 1, as shown in formula 1 ' Macrolides compound and its pharmaceutically acceptable salt content preferred mass percentage composition 0.5%~99%；Into one Step preferably 50%~97%, the mass percentage are macrolides compound as shown in Equation 1, as shown in formula 1 ' The gross mass of macrolides compound and its pharmaceutically acceptable salt accounts for the percentage of pharmaceutical composition gross mass；It is described Beta-lactam antibiotic mass percentage preferably 1%~99.5%, further preferred 3%~50%；The matter The quality that percentage composition is beta-lactam antibiotic is measured, the percentage of pharmaceutical composition gross mass is accounted for；Heretofore described The summation of the mass fraction of each component is 100% in pharmaceutical composition.

In the present invention, the beta-lactam antibiotic is beta-lactam antibiotic conventional in the art, is referred to In molecule containing by four molecular beta-lactam nucleus of original antibiotic, the preferably clinical most common penicillin antibiotics, One in cephalosporins, carbapenem antibiotic, cephamycin-type antibiotic and monocycle beta-lactam antibiotics Kind is a variety of.The preferred penicillin of the penicillin antibiotics, benzyl penicillin, Benzylpenicillin sodium salt, ospeneff, ampicillin, Ampicillin, carbenicillin sodium, oxacillin, Cloxacillin, dicloxacillin, flucloxacillin, Benzathine, furan cloth west One of woods, Amoxicillin, mezlocillin, nefcillin, Ticarcillin, azlocillin, Piperacillin and Mecillinam are more Kind；One of further preferred Benzylpenicillin sodium salt, ampicillin, carbenicillin sodium and oxacillin sodium are a variety of.Described The preferred cefalexin of cephalosporins, Cefotiam, cefadroxil, cephazoline, cefradine, Cefaclor, The appropriate human relations pivoxil of cefuroxime, cefpiramide, cefathiamidine, Cefprozil, ceftriaxone, cephalo, Cefodizime, cefetamet Ester, Cefixime, Cefpodoxime Proxetil, cefotaxime, cefotaxime potassium, Cefdinir, cephalo draw oxygen, ceftezole, cephalo thiophene One of oxime, cefoperazone, cefoxitin, Cefamandole, Cefpirome, Cefepime and Cefuzonam are a variety of；Into one Walk preferred cefradine, cefoxitin, cephazoline, cefalexin, Cefamandole, Cefotiam, Cefaclor, cephalo furan One of pungent, ceftriaxone, cefoperazone, cefotaxime potassium, cefotaxime, Cefepime and Cefodizime are a variety of.Institute One of the preferred Imipenem of the carbapenem antibiotic stated, Meropenem and Panipenem are a variety of；Further preferably Imipenem and/or Meropenem.The preferred Cefoxitin of cephamycin-type antibiotic, cefoxitin sodium, cefmetazole, head One of spore U.S. azoles sodium, cefotetan and Cefminox or a variety of, further preferred Cefoxitin, cefoxitin sodium, cephalo One of U.S. azoles and cefmetazole sodium are a variety of.The preferred aztreonam of the monocycle beta-lactam antibiotics.

In pharmaceutical composition of the present invention, the macrolides compound as shown in Equation 1, as shown in formula 1 ' Macrolides compound and its pharmaceutically acceptable salt gross mass, the mass ratio with the beta-lactam antibiotic It is preferred that >=1:1；The mass ratio refers in the pharmaceutical composition, the macrolides chemical combination as shown in Equation 1 Object, the gross mass of macrolides compound and its pharmaceutically acceptable salt as shown in formula 1 ' and beta-lactam antibiotic Quality ratio.The macrolides compound as shown in Equation 1, the macrolides compound as shown in formula 1 ' and In the solution that its pharmaceutically acceptable salt and water are formed, the macrolides compound as shown in Equation 1, shown in 1 ' The ratio of the gross mass and liquor capacity of macrolides compound and its pharmaceutically acceptable salt preferably >=8 μ g/mL.

The present invention also provides the pharmaceutical compositions to prepare the medicine for inhibiting methicillin-resistant staphylococcus aureus Application in object.

In the present invention, the methicillin-resistant staphylococcus aureus (MRSA) is resistance to methoxy west conventional in the art Woods staphylococcus aureus, preferably methicillin-resistant staphylococcus aureus mode bacterium；The methicillin-resistant staphylococcus Portugal The preferred MRSA ATCC43300 of grape coccus mode bacterium (Methicillin-resistant Staphylococcus aureus ATCC43300, i.e. MRSA ATCC43300).ATCC is American Type Culture collection warehousing (American type culture Collection the MRSA ATCC43300 that writes a Chinese character in simplified form) is its mode standard bacterium.

In the present invention, the alkyl not defined especially refers to the not alkyl replaced other substituent groups in addition to alkyl, packet Include linear or branched alkyl group, such as heretofore described C₁~C₄Alkyl include methyl, ethyl, propyl, isopropyl, butyl And isobutyl group；Heretofore described C₁~C₅Alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, amyl, Tert-butyl, isopentyl and neopentyl.

In the present invention, the alkoxy not defined especially refers to the not alcoxyl replaced other substituent groups in addition to alkyl Base, including straight or branched alkoxyl, such as heretofore described C₁~C₄Alkoxy include methoxyl group, ethyoxyl, the third oxygen Base, isopropoxy, butoxy and isobutoxy.

In the present invention, the heteroaryl not defined especially refers in heteroaryl replaced unsubstituted base, such as the present invention The C₄~C₅Heteroaryl includes thienyl, furyl, pyrrole radicals and pyridyl group.

In the present invention, the phenyl not defined especially refers to phenyl replaced unsubstituted base.

Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can any combination to get the present invention it is each preferably Example.

Heretofore described room temperature refers to environment temperature, is 10 DEG C~35 DEG C.

The reagents and materials used in the present invention are commercially available.

The positive effect of the present invention is that: macrolides compound 1 of the invention, macrolides compound 1 ', one of salt of the salt of macrolides compound 1 and macrolides compound 1 ' or it is a variety of with beta-lactam When antibiotic is used in conjunction with, it can significantly increase beta-lactam antibiotic and inhibit methicillin-resistant staphylococcus aureus Effect.This is a kind of Novel synergistic agent, and external synergistic effect is good, can alleviate methicillin-resistant staphylococcus aureus It (MRSA) is a kind of drug with the good prospect of marketing to the drug resistance of beta-Lactam antibiotic.

Specific embodiment

The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient The selection of product specification.

The preparation of 1 9- hydrazone clarithromycin (SIPI8901) of embodiment

Clarithromycin (10g, 13.37mmol) is dissolved in methanol (80mL), is added hydrazine acetate (36.9g, 0.4mol), 70 DEG C It is heated to reflux 48h.It after revolving removes part methanol, is added water (200mL), adjusts pH to 9~10, mistake with 3N NaOH aqueous solution Filter, filter cake washing, dry crude white solid 10.7g.1g crude product FLASH column chromatography for separation is taken to obtain product 0.68g (yield 72.8%, HPLC purity 85%).

The preparation of 2 3- descladinosylation -3- hydroxyl -9- hydrazone clarithromycin (SIPI8903) of embodiment

9- hydrazone clarithromycin (1.5g, 2mmol) is dissolved in 10mL1N aqueous hydrochloric acid solution, 25 DEG C of stirring 4h.Dichloromethane is added Alkane 10mL adjusts pH to 9-10, liquid separation with 3N sodium hydroxide, and water layer is extracted with 5mL methylene chloride, merges dichloromethane layer, 10mL washing, after silica gel mixed sample is added after saturated sodium-chloride is dry, FLASH column chromatography for separation obtains product 0.85g.(yield 71.4%, HPLC purity 85%).

The preparation of 3 3- descladinosylation -3- hydroxyl -9- isopropylidene hydrazone clarithromycin (SIPI8904) of embodiment

3- descladinosylation -3- hydroxyl -9- hydrazone clarithromycin (1.2g, 2mmol) is dissolved in 5mL acetone, and 56 DEG C are heated back 4h is flowed, is evaporated to obtain crude product, after silica gel mixed sample, FLASH column chromatography for separation obtains product 0.5g.(yield 42.4%, HPLC purity 89.6%).

MS(ESI⁺,m/e):644.85[M+H]⁺

The preparation of 4 9- isopropylidene hydrazone clarithromycin (SIPI8231) of embodiment

9- hydrazone clarithromycin (1g, 1.3mmol) is dissolved in 5mL acetone, and 56 DEG C are heated to reflux 4h, and reaction solution is evaporated to obtain crude product 1.1g.FLASH column chromatography for separation obtains product 1.04g (yield 98.5%, HPLC purity 93.7%).

The preparation of 52 '-O- acetyl group -9- isopropylidene hydrazone clarithromycin of embodiment

9- isopropylidene hydrazone clarithromycin (11.1g, 13.8mmol) is dissolved in 40mL methylene chloride, and acetic anhydride is added (1.9mL, 20mmol), 25 DEG C of stirring 4h.Add water 50mL, adjusts pH to 9-10, liquid separation with 3N sodium hydrate aqueous solution, water layer is used Methylene chloride (20mL) extracting, merges dichloromethane layer, and water (50mL) washes, and after saturated salt solution is dry, rotates dry crude product 11.5g, crude yield 99.5%.

The preparation of 62 '-O- acetyl group -3- descladinosylation -3- hydroxyl -9- isopropylidene hydrazone clarithromycin of embodiment

It is (described in 1N hydrochloric acid 95mL that 2 '-O- acetyl group -9- isopropylidene hydrazone clarithromycin 12.7g, which are dissolved in molar concentration, Molar concentration refer to the mole of hydrogen chloride and the ratio of aqueous hydrochloric acid solution total volume), 25 DEG C of stirring 3h.Methylene chloride is added 40mL adjusts pH to 9~10, liquid separation with 3N NaOH aqueous solution, and water layer extracts (20mL × 2) with methylene chloride, merges dichloromethane Alkane layer is washed (50mL × 2), and saturated common salt washing is spin-dried for obtaining white solid 9.7g, yield 94.0%.

The preparation of 72 '-O- acetyl group -3- descladinosylation -3- oxo -9- isopropylidene hydrazone clarithromycin of embodiment

2 '-O- acetyl group -3- descladinosylation -3- hydroxyl -9- isopropylidene hydrazone clarithromycin (2.06g, 3mmol) are dissolved in EDCI (4.03g, 21mmol), DMSO (4.7g, 60mmol), TFAPy (pyridinium trifluoroacetate) is added in 25mL methylene chloride (2.03g, 10.5mmol), 25 DEG C of stirring 1h.Water 25mL is added, adjusts pH to 9-10, liquid separation with 3N sodium hydroxide, water layer is used The extracting of 5mL methylene chloride merges dichloromethane layer, and 25mL washing is spin-dried for obtaining crude product 1.8g after saturated sodium-chloride is dry, crude product is received Rate 87.4%.

The preparation of 8 3- descladinosylation -3- oxo -9- hydrazone clarithromycin (SIPI8907) of embodiment

2 '-O- acetyl group -3- descladinosylation -3- oxo -9- isopropylidene hydrazone clarithromycin (1g, 1.5mmol) are dissolved in 5mL methanol, addition mass percent are 85% hydrazine hydrate 0.6mL, and 65 DEG C are heated to reflux 4h.Add 10mL water, 10mL methylene chloride, PH to 9-10, liquid separation are adjusted with 3N sodium hydroxide, water layer is extracted with 5mL methylene chloride, merges dichloromethane layer, is washed, saturation Salt washing, is evaporated rear FLASH column chromatography for separation and obtains product 0.4g (yield 45.5%, HPLC purity 85%).

The preparation of 9 3- descladinosylation -3- oxo -9- isopropylidene hydrazone clarithromycin (SIPI8908) of embodiment

2 '-O- acetyl group -3- descladinosylation -3- oxo -9- isopropylidene hydrazone clarithromycin (1g, 1.5mmol) are dissolved in 5mL methanol, 65 DEG C are heated to reflux 4h.Add 10mL water, 10mL methylene chloride adjusts pH to 9-10, liquid separation, water with 3N sodium hydroxide Layer is extracted with 5mL methylene chloride, merges dichloromethane layer, washing, and saturated common salt washing is evaporated rear FLASH column chromatography for separation and obtains Product 0.5g (yield 53%, HPLC purity 88.0%).

Embodiment 10 3- descladinosylation -3- oxo -9- (4- methoxybenzene ethylidene hydrazone) clarithromycin (SIPI8909) Preparation

3- descladinosylation -3- oxo -9- hydrazone clarithromycin (2.0g, 3.3mmol) is dissolved in 10mL methanol, is added to first Oxygroup acetophenone (1.2g, 9.9mmol), glacial acetic acid (0.6mL, 9.9mmol), 65 DEG C are heated to reflux 4h.10mL water, 10mL is added Methylene chloride adjusts pH to 9-10, liquid separation with 3N sodium hydroxide, and water layer is extracted with 5mL methylene chloride, merges dichloromethane layer, Washing, saturated common salt washing, is evaporated rear FLASH column chromatography for separation and obtains product 1.5g (yield 63%, HPLC purity 84.9%).

11 2 '-O- acetyl group -3- descladinosylation -3-O- phenylacetyl group -9- isopropylidene hydrazone clarithromycin of embodiment Preparation

2 '-O- acetyl group -3- descladinosylation -3- hydroxyl -9- isopropylidene hydrazone clarithromycin (4.9g, 7.1mmol) are molten In methylene chloride 20mL, it is added phenylacetic acid (2.9g, 21mmol), EDCI (4.0g, 21mmol), DMAP (4-dimethylaminopyridine) 0.1g, 25 DEG C of stirring 8h.Add water 20mL, adjusts pH to 9-10, liquid separation with 3N sodium hydroxide, water layer is taken out with 10mL methylene chloride It mentions, merges organic layer, washing, saturated salt solution is dry, is evaporated to obtain crude product 6.6g, crude yield 115.0%.

The preparation of 12 3- descladinosylation -3-O- phenylacetyl group -9- hydrazone clarithromycin (SIPI8911) of embodiment

2 '-O- acetyl group -3- descladinosylation -3-O- phenylacetyl group -9- isopropylidene hydrazone clarithromycin (intermediate compounds Object 1 ' -2) crude product 3.3g is dissolved in 20mL methanol, be added mass percent be 65 DEG C of 85% hydrazine hydrate (1.2mL, 20.5mmol) plus Heat reflux 4h.It is evaporated rear FLASH column chromatography for separation and obtains product 1.6g (with 1 ' -2 collecting rate 62.0% of compound, HPLC purity 86.5%).

The preparation of 13 hydrazine acetate of embodiment

The hydrazine hydrate (11.4mL, 0.2mol) that mass percent is 85% is added in round-bottomed flask, is slowly added dropwise under ice bath Glacial acetic acid (11.4mL, 0.2mol) controls temperature at 0-10 DEG C.40min is stirred to react for 25 DEG C after being added dropwise.It is spin-dried for, it is cooling It precipitates crystal, obtains white crystal 18.2g, yield 98.9%.

The preparation of 14 pyridinium trifluoroacetate salt of embodiment

Pyridine 16.1mL is dissolved in 20mL water, and trifluoroacetic acid aqueous solution is added dropwise under 0 DEG C of ice bath, and (trifluoroacetic acid 15.4mL is dissolved in It is made in 20mL water), 25 DEG C of stirring 18h after dripping are spin-dried for obtaining white solid 36.4g, yield 94.4%.

The preparation of 15 9- isobutyryl hydrazone clarithromycin of embodiment

It takes isobutyric acid 0.93mL (10mmol) in a round bottom flask, 18mL methylene chloride is added and dissolves, addition DCC (N, N '- Dicyclohexylcarbodiimide) (8.5mmol, 1.75g), stirring addition 9- hydrazone clarithromycin (5mmol, 3.81g) after twenty minutes, 25 DEG C stirring 18 hours.Filtering removes insoluble matter, and filtrate adds water, and 3N NaOH tune pH to 9.7 separates organic phase, water phase dichloro Methane extracts three times, merges organic phase, and through washing, saturated common salt washing, natrium carbonicum calcinatum is dried, filtered, and filtrate decompression is evaporated, Obtain crude product 4.1g, crude yield 98.6%.

The preparation of 16 2 '-O- acetyl group -9- isobutyryl hydrazone clarithromycin of embodiment

9- isobutyryl hydrazone clarithromycin crude product 4.1g is set in a round bottom flask, and the dissolution of 15mL methylene chloride, stirring is added Lower addition acetic anhydride (7.4mmol, 0.7mL), 25 DEG C are stirred 3 hours.15mL is added into reaction solution, with 3N sodium hydroxide solution PH to 9.7 is adjusted, liquid separation, water phase is extracted with methylene chloride, merges organic phase, washing, saturated common salt washing, filtering, filtrate rotation Do to obtain white solid 4.38g, crude yield 101.9%.

The preparation of 17 2 '-O- acetyl group -3- descladinosylation -3- hydroxyl -9- isobutyryl hydrazone clarithromycin of embodiment

In a round bottom flask, 1N ethanol solution hydrochloride is added in 2 '-O- acetyl group -9- isobutyryl hydrazone clarithromycin 4.38g 2mL, 25 DEG C are stirred 5 hours.Into reaction solution be added methylene chloride 30mL, water 30mL, with 3N sodium hydroxide solution adjust pH to 9.7, liquid separation, water phase is extracted with methylene chloride, merges organic phase, washing, saturated common salt washing, filtering, filtrate is spin-dried for white Solid 3.74g, crude yield 96.0%.

The preparation of 18 2 '-O- acetyl group -3- descladinosylation -3- oxo -9- isobutyryl hydrazone clarithromycin of embodiment

EDCHCl (22.6mmol, 4.33g) is added into round-bottomed flask to be dissolved with methylene chloride 20mL afterwards, DMSO is added (dimethyl sulfoxide) (45.3mmol, 3.54g), 25 DEG C stirring 30 minutes after be added on walk product 3.24g and PyHCl (pyrrole Thiamine hydrochloride) (22.6mmol, 2.61g), 25 DEG C are stirred 24 hours.40mL water, liquid separation, water phase dichloro are added into reaction solution Methane extracting, merges organic phase, washing, and saturated common salt washes back spin and does to obtain faint yellow solid 2.22g, crude yield 68.3%.

The preparation of 19 3- descladinosylation -3- oxo -9- isobutyryl hydrazone clarithromycin (SIPI8369) of embodiment

2 '-O- acetyl group -3- descladinosylation -3- oxo -9- isobutyryl hydrazone clamycin 2 .22g are dissolved in 20mL methanol In, 65 DEG C are heated to reflux 3h, are spin-dried for obtaining solid 2.04g, and column chromatography for separation [methanol-chloroform (1:10)] obtains white foaming material 0.45g, in terms of clarithromycin, yield 15.5%.

MS(ESI⁺,m/e):672.44[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 8.49 (s, 1H, 9=N-NH),

¹³CNMR(400MHz,CDCl₃) δ (ppm): 205.88 (3-C=O), 178.79 (9-NH-CO-), 169.97 (1-C =O) 165.96 (9 > C=N-)

The preparation of 20 9- isopropylidene hydrazone clarithromycin of embodiment

9- hydrazone clarithromycin 10.7g is dissolved in 50mL acetone, and 56 DEG C are heated to reflux 4h, is rotated away solvent and is obtained white solid 12.4g。

The preparation of 21 3- descladinosylation -3- oxo -9- hydrazone clarithromycin of embodiment

2 '-O- acetyl group -3- descladinosylation -3- oxo -9- isopropylidene hydrazone clarithromycin (5.2g, 35.5mmol) are molten In 40mL methanol, the hydrazine hydrate that mass percent is 85% is added, and (mass percent refers to that the quality of hydrazine accounts for hydration The percentage of hydrazine gross mass) (2mL, 35.5mmol), heat 65 DEG C of reflux 4h.Add water 30mL, methylene chloride 20mL, liquid separation, water Layer extracts (10mL × 2) with methylene chloride, merges dichloromethane layer, washes (50mL × 2), and saturated common salt washing is spin-dried for yellow Color solid 4.1g.Column chromatography for separation obtains product 1.28g, total recovery 31.5% in terms of clarithromycin, HPLC content 87%.MS(ESI⁺,m/e):602.30[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 4.02 (s, 2H, 9=N-NH₂),

¹³CNMR(400MHz,CDCl₃) δ (ppm): 206.21 (3-C=O), 169.95 (1-C=O), 167.12 (9 > C= N-)

22 3- descladinosylation -3- oxo -9- benzoyl hydrazone clarithromycin (SIPI8373) of embodiment

P-methoxybenzoic acid (1.52g, 10mmol) is dissolved in 10mL methylene chloride, is added DCC (2.06g, 10mmol), 30h is stirred in 25 DEG C of stirring 30min, 25 DEG C of addition 3- descladinosylation -3- oxo -9- hydrazone clarithromycin (1.2g, 2mmol).Filtering, Filtrate adds water 15mL, adjusts pH to 9~10, liquid separation with 3N NaOH aqueous solution, and water layer extracts (10mL × 2) with methylene chloride, closes And dichloromethane layer, it washes (30mL × 2), saturated common salt washing is spin-dried for, and FLASH pillar layer separation obtains white solid 0.26g, Yield 17.7%, TLC content 85%.

MS(ESI⁺,m/e):736.42[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 8.74 (s, 1H, 9=N-NH), 6.93-7.98 (4H, 9-Ph), 3.69- 3.81(3H,9-Ph-OCH₃)

¹³CNMR(400MHz,CDCl₃) δ (ppm): 206.11 (3-C=O), 169.94 (1-C=O), 164.96 (9 > ), CONH- 162.40 (9 > C=N-), 113.53-131-62,163.28 (Ph-6C)

The preparation of 23 3- descladinosylation -3- oxo -9- cyclopentylene hydrazone clarithromycin (SIPI8381) of embodiment

3- descladinosylation -3- oxo -9- hydrazone clarithromycin (1g, 1.67mmol) is dissolved in 5mL cyclopentanone, 25 DEG C of stirrings 4h.Add water 15mL, methylene chloride 15mL, adjusts pH to 9~10 with 3N NaOH aqueous solution, liquid separation, water layer is extracted with methylene chloride (10mL) merges dichloromethane layer, washes (30mL × 2), and saturated common salt washing is spin-dried for, FLASH separates to obtain white solid 0.35g, yield 31.6%, HPLC content 96.4%.MS(ESI⁺,m/e):668.53[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 2.41-2.50 (4H, 2,5 4H of cyclopentanone)

¹³CNMR(400MHz,CDCl₃) δ (ppm): 205.59 (3-C=O), 177.13-179.22 (2C, 9- azine), (169.41 1-C=O)

Embodiment 24 3- descladinosylation -3- oxo -9- (4- methyl-pentane -2- subunit) hydrazone clarithromycin (SIPI8382) preparation

3- descladinosylation -3- oxo -9- hydrazone clarithromycin (1g, 1.67mmol) is dissolved in 5mL methanol, and 4- first is added Base -2 pentanone (0.25,0.31mmol), glacial acetic acid (0.05mL, 0.84mmol), is heated to reflux 3h.Add water 15mL, methylene chloride 15mL adjusts pH to 9~10, liquid separation with 3N NaOH aqueous solution, and water layer extracts (10mL) with methylene chloride, merges methylene chloride Layer, wash (30mL × 2), saturated common salt washing, be spin-dried for faint yellow solid 1.0g, FLASH post separation obtains 0.49g, yield 43.1%, HPLC content 92.0%.

MS(ESI⁺,m/e):684.58[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 0.84-0.94 (6H, 9-4 ' dimethyl)

¹³CNMR(400MHz,CDCl₃) δ (ppm): 205.49 (3-C=O), 169.46-168.99 (2C, 9- azine), (178.43 1-C=O)

The preparation of 25 3- descladinosylation -3- oxo -9- (biphenyl ethylidene) hydrazone clarithromycin (SIPI8383) of embodiment

3- descladinosylation -3- oxo -9- hydrazone clarithromycin (0.6g, 1mmol) is dissolved in 10mL methanol, and biphenyl second is added Ketone (0.2g, 3mmol), glacial acetic acid (0.17mL, 3mmol), 65 DEG C are heated to reflux 3h.Water 10mL, methylene chloride 10mL is added to use 3N NaOH aqueous solution adjusts pH to 9~10, liquid separation, and water layer extracts (10mL) with methylene chloride, merges dichloromethane layer, washing (30mL × 2), saturated common salt washing, are spin-dried for obtaining faint yellow solid 0.8g.FLASH pillar layer separation obtains 0.37g product, yield 47.6%, HPLC content 92.4%.

MS(ESI+,m/e):780.31[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.26-7.96 (9H, 9- biphenyl)

¹³CNMR(400MHz,CDCl₃) δ (ppm): 205.59 (3-C=O), 178.98 (1-C=O), 160.48-169.42 (2C-9 azine), 126.98-142.43 (12C, 9- biphenyl)

The system of embodiment 26 3- descladinosylation -3- oxo -9- (2- hydroxyl benzal) hydrazone clarithromycin (SIPI8384) It is standby

3- descladinosylation -3- oxo -9- hydrazone clarithromycin (1g, 1.67mmol) is dissolved in 10mL methanol, and adjacent hydroxyl is added Benzaldehyde (0.52mL, 5mmol), glacial acetic acid (0.29mL, 5mmol), 65 DEG C are heated to reflux 5h.Add water 15mL, methylene chloride 15mL adjusts pH to 9~10, liquid separation with 3N NaOH aqueous solution, and water layer extracts (10mL) with methylene chloride, merges methylene chloride Layer is washed (30mL × 2), and saturated common salt washing is spin-dried for obtaining 0.35g product, yield 29.9%, HPLC content 91.8%.

MS(ESI⁺,m/e):706.30[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 11.51 (1H, phenolic hydroxyl groups), 8.44 (9-N=CH) 7.25-7.34 (4H, 9- phenyl ring)

¹³CNMR(400MHz,CDCl₃) δ (ppm): 205.73 (3-C=O), 169.63 (1-C=O), 183.61 (phenyl ring 1 Position), 159.46,169.37 (2C-9 azines), 162.63 (9-C=N), 132.04-132.64 (phenyl ring 4,6), 116.77- 119.47 (phenyl ring 1,3,5)

Embodiment 27 3- descladinosylation -3- oxo -9- (4- methoxybenzene ethylidene) hydrazone clarithromycin (SIPI8385) Preparation

3- descladinosylation -3- oxo -9- hydrazone clarithromycin (1g, 1.67mmol) is dissolved in 10mL methanol, is added to methoxy Benzoylformaldoxime (0.75g, 5mmol), glacial acetic acid (0.29mL, 5mmol), 65 DEG C are heated to reflux 4h.Add water 15mL, methylene chloride 15mL adjusts pH to 9~10, liquid separation with 3N NaOH aqueous solution, and water layer extracts (10mL) with methylene chloride, merges methylene chloride Layer is washed (30mL × 2), and saturated common salt washing is spin-dried for obtaining 0.39g product, yield 32.0%, HPLC content 90.6%.

MS(ESI⁺,m/e):734.23[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.83-7.85 (2H, 9- phenyl ring 2,6), 6.90-6.92 (2H, 9- benzene 3,5, ring), 3.84-3.87 (phenyl ring-OCH₃)

¹³CNMR(400MHz,CDCl₃) δ (ppm): 205.56 (3-C=O), 178.70 (1-C=O), 160.99-169.37 (2C-9 azine), 160.36 (9- phenyl ring 4), 113.67-131.20 (5C, 9- phenyl ring)

The system of 28 3- descladinosylation -3- oxo -9- (3- nitrobenzal) hydrazone clarithromycin (SIPI8386) of embodiment It is standby

3- descladinosylation -3- oxo -9- hydrazone clarithromycin (0.55g, 0.92mmol) is dissolved in 10mL methanol, nitre between addition Benzaldehyde (0.42g, 2.8mmol), glacial acetic acid (0.16mL, 2.8mmol), 65 DEG C are heated to reflux 6h.Add water 10mL, dichloromethane Alkane 10mL adjusts pH to 9~10, liquid separation with 3N NaOH aqueous solution, and water layer extracts (10mL) with methylene chloride, merges dichloromethane Alkane layer is washed (30mL × 2), and saturated common salt washing is spin-dried for.FLASH post separation obtains faint yellow solid 0.37g, yield 55.2%, HPLC content 91.9%.MS(ESI⁺,m/e):735.35[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 8.39 (1H, 9-N=CH), 8.64 (1H, phenyl ring 6), 7.64-8.29 (3H, 9- phenyl ring 3,4,5),

¹³CNMR(400MHz,CDCl₃) δ (ppm): 205.55 (3-C=O), 185.40 (1-C=O), 1148.81,169, 40 (9- azines), 156.42 (9- phenyl ring 2), 122.43-136.25 (9- phenyl ring)

Embodiment 29 3- descladinosylation -3- oxo -9- (2,6 difluorophenyl benzal) hydrazone clarithromycin (SIPI8387) preparation

3- descladinosylation -3- oxo -9- hydrazone clarithromycin (1g, 1.67mmol) is dissolved in 10mL methanol, and 2,6- bis- is added Fluorobenzaldehyde (0.71mL, 5mmol), glacial acetic acid (0.29mL, 5mmol), 65 DEG C are heated to reflux 4h.Add water 15mL, methylene chloride 15mL adjusts pH to 9~10, liquid separation with 3N NaOH aqueous solution, and water layer extracts (10mL) with methylene chloride, merges methylene chloride Layer is washed (30mL × 2), and saturated common salt washing is spin-dried for.FLASH pillar layer separation obtains product 0.18g, yield 14.9%, HPLC Content 94.9%.MS(ESI⁺,m/e):726.41[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 8.52 (1H, 9-N=CH), 7.36 (1H, phenyl ring 4), 6.93-6.97 (2H, 9- phenyl ring 3,5),

¹³CNMR(400MHz,CDCl₃) δ (ppm): 205.68 (3-C=O), 184.47 (1-C=O), 149.82,169.47 (9- azine), 160.42-163.05 (9- phenyl ring 2,6), 111.83-112.09 (9- phenyl ring 3,5)

Embodiment 30 3- descladinosylation -3- oxo -9- (valeryl para-totuidine -4- subunit) hydrazone clarithromycin (SIPI8388) preparation

4- oxo-valeryl para-totuidine

Para-totuidine (2.14g, 0.02mol) is dissolved in 25mL methylene chloride, addition levulic acid (2.78g, 0.024mol), 1- hydroxy benzo triazole (HoBT, CAS:2592-95-2) (3.24g, 0.024mol), triethylamine (3.4mL), EDCHCl (4.6g, 0.024mol) is added portionwise, 30min is stirred at room temperature after adding.Washing, saturated common salt washing, uses ethyl alcohol Recrystallize to obtain gray solid 1.56g, yield 38.0%.

3- descladinosylation -3- oxo -9- hydrazone clarithromycin (0.4g, 0.67mmol) is dissolved in 10mL methanol, and 4- oxygen is added Generation-valeryl para-totuidine (0.49g, 2.7mmol), glacial acetic acid (0.2mL, 2.7mmol), 65 DEG C are heated to reflux 4h.Add water 15mL, Methylene chloride 15mL adjusts pH to 9~10, liquid separation with 3N NaOH aqueous solution, and water layer extracts (10mL) with methylene chloride, merges Dichloromethane layer is washed (30mL × 2), and saturated common salt washing is spin-dried for.FLASH separates to obtain product 0.16g, yield 30.5%, HPLC content 87.7%.

MS(ESI+,m/e):789.44[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.72 (1H, 9-CO-NH), 7.35-7.37 (2H, phenyl ring 2,6), 7.10-7.12 (2H, 9- phenyl ring 3,5)

¹³CNMR(400MHz,CDCl₃) δ (ppm): 205.69 (3-C=O), 178.72 (pentanamide-C=O), 169.47 (1-C=O), 164.84 (9-C=N), 119.69-133.59 (phenyl ring)

Embodiment 31 3- descladinosylation -3- oxo -9- (butyrylamino pyridine -3- subunit) hydrazone clarithromycin (SIPI8389) preparation

2- (3- oxo-butyryl)-aminopyridine diketene (1.68g, 0.02mol) is dissolved in 10mL methylene chloride, in batches It is added 2-aminopyridine (1.89g, 0.02mol), 25 DEG C of stirring 2h, revolving removes solvent and obtains yellow solid, uses ethyl alcohol recrystallization Obtain white solid 2.5g, yield 70.6%.

MS(ESI⁺,m/e):179.09[M+H]⁺；201.07[M+Na]⁺；379.13[2M+Na]⁺

3- descladinosylation -3- oxo -9- hydrazone clarithromycin (0.3g, 0.5mmol) is dissolved in 10mL methanol, and 2- (3- is added Oxo-butyryl)-aminopyridine (0.18g, 1mmol), glacial acetic acid (0.03mL, 0.5mmol), 65 DEG C are heated to reflux 4h.Add water 15mL, methylene chloride 15mL adjust pH to 9~10, liquid separation with 3N NaOH aqueous solution, and water layer extracts (10mL) with methylene chloride, Merge dichloromethane layer, wash (30mL × 2), saturated common salt washing is spin-dried for.FLASH separates to obtain product 0.17g, yield 44.7%, TLC content 85%.

MS(ESI⁺,m/e):762.35[M+H]⁺

Embodiment 32 3- descladinosylation -3- oxo -9- (butyryl para-totuidine -3- subunit) hydrazone clarithromycin (SIPI8390) preparation

3- oxo-butyryl para-totuidine diketene (1.68g, 0.02mol) is dissolved in 10mL methylene chloride, is added portionwise pair Toluidines (2.14g, 0.02mol), 25 DEG C of stirring 2h, revolving remove solvent and obtain yellow solid, obtained with ethyl alcohol recrystallization white solid Body 1.77g, yield 46.3%.

3- descladinosylation -3- oxo -9- hydrazone clarithromycin (0.2g, 0.33mmol) is dissolved in 10mL methanol, and 3- oxygen is added Generation-butyryl para-totuidine (0.25g, 1.33mmol), glacial acetic acid (0.08mL, 1.33mmol), 65 DEG C are heated to reflux 4h.Add water 15mL, methylene chloride 15mL adjust pH to 9~10, liquid separation with 3N NaOH aqueous solution, and water layer extracts (10mL) with methylene chloride, Merge dichloromethane layer, wash (30mL × 2), saturated common salt washing is spin-dried for.FLASH pillar layer separation obtains white solid 0.2g, Yield 77.6%, TLC content 85%.

MS(ESI⁺,m/e):775.33[M+H]⁺

Embodiment 33 3- descladinosylation -3- oxo -9- (valeryl P-nethoxyaniline -4- subunit) hydrazone clarithromycin (SIPI8391) preparation

4- oxo-valeryl is to methyl oxyaniline

Methyl oxyaniline (2.46g, 0.02mol) is dissolved in 25mL methylene chloride, addition levulic acid (2.78g, 0.024mol), 1- hydroxy benzo triazole (HoBT, CAS:2592-95-2) (3.24g, 0.024mol), triethylamine (3.4mL), EDCHCl (4.6g, 0.024mol) is added portionwise, 25 DEG C of stirring 30min after adding.Washing, saturated common salt washing, uses ethyl alcohol Recrystallize to obtain gray solid 1.56g, yield 38.0%.MS(ESI⁺,m/e):192.15[M+H]⁺；214.13[M+Na]⁺； 405.25[2M+Na]⁺

3- descladinosylation -3- oxo -9- hydrazone clarithromycin (0.3g, 0.5mmol) is dissolved in 10mL methanol, and 4- oxygen is added Generation-valeryl is to methyl oxyaniline (0.44g, 2mmol), and glacial acetic acid (0.15mL, 2mmol), 65 DEG C are heated to reflux 3h.Add water 15mL, Methylene chloride 15mL adjusts pH to 9~10, liquid separation with 3N NaOH aqueous solution, and water layer extracts (10mL) with methylene chloride, merges Dichloromethane layer is washed (30mL × 2), and saturated common salt washing is spin-dried for.FLASH separates to obtain white solid 0.25g, yield 62.5%, HPLC content 87.4%.MS(ESI⁺,m/e):805.56[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.68 (1H, 9-CO-NH-), 7.37-7.39 (2H, phenyl ring 2,6), (6.84-6.86 2H, phenyl ring 3,5)

¹³CNMR(400MHz,CDCl₃) δ (ppm): 205.68 (3-C=O), 178.69 (1-C=O), 170.42 (9-CO- ), NH- 169.47 (9-C=N-), 164.86 (9-N=C-), 156.34 (phenyl ring 4), 114.19-131.29 (phenyl ring)

Embodiment 34 3- descladinosylation -3- oxo -9- (phenylpropyl alcohol alkane -1- subunit) hydrazone clarithromycin (SIPI8392) Preparation

3- descladinosylation -3- oxo -9- hydrazone clarithromycin (0.6g, 1mmol) is dissolved in 5mL methanol, and propiophenone is added (0.16mL, 1.2mmol), glacial acetic acid (0.03mL, 0.5mmol), 65 DEG C are heated to reflux 3h.Add water 10mL, methylene chloride 10mL, PH to 9~10, liquid separation are adjusted with 3N NaOH aqueous solution, water layer extracts (5mL) with methylene chloride, merges dichloromethane layer, washing (20mL × 2), saturated common salt washing, are spin-dried for obtaining faint yellow solid 0.67g.FLASH pillar layer separation obtains gray solid 0.3g, receives Rate 41.9%, HPLC content 87.6%.

MS(ESI⁺,m/e):718.36[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.73-7,88 (2H, 9- phenyl ring 2,6), 7.20-7.44 (3H, phenyl ring 3,4,5)

¹³CNMR(400MHz,CDCl₃) δ (ppm): 205.62 (3-C=O), 179.44 (1-C=O), 166.19,169.42 (9- azine), 137.51 (phenyl ring 1), 127.49-130.14 (phenyl ring)

The system of embodiment 35 3- descladinosylation -3- oxo -9- (3- hydroxyl benzal) hydrazone clarithromycin (SIPI8393) It is standby

3- descladinosylation -3- oxo -9- hydrazone clarithromycin (0.6g, 1mmol) is dissolved in 15mL methanol, hydroxyl between addition Benzaldehyde (0.37g, 3mmol), glacial acetic acid (0.17mL, 3mmol), 65 DEG C are heated to reflux 6h.Add water 15mL, methylene chloride 15mL adjusts pH to 9~10, liquid separation with 3N NaOH aqueous solution, and water layer extracts (10mL) with methylene chloride, merges methylene chloride Layer is washed (30mL × 2), and saturated common salt washing is spin-dried for obtaining gray solid 0.83g.FLASH pillar layer separation separates to obtain 0.26g Product, yield 36.3%, HPLC content 85.9%.MS(ESI⁺,m/e):706.54[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 8.32 (1H, 9- phenolic hydroxyl groups), 7.24-7.31 (3H, phenyl ring 4,5,6), 6.93 (1H, phenyl ring 2), 5.58 (1H, phenyl ring 3-OH)

¹³CNMR(400MHz,CDCl₃) δ (ppm): 205.77 (3-C=O), 183.48 (1-C=O), 156.42,169.58 (9- azine), 158.86 (9- phenyl ring 3), 129.94-136.00 (phenyl ring 1,5), 114.49-120.89 (phenyl ring 2,4,6 Position)

Embodiment 36 3- descladinosylation -3- oxo -9- (2- pyrroles ethane -1- subunit) hydrazone clarithromycin (SIPI8394) preparation

3- descladinosylation -3- oxo -9- hydrazone clarithromycin (0.6g, 1mmol) is dissolved in 5mL methanol, 2- second between addition Acyl pyrroline (0.13g, 1.2mmol), glacial acetic acid (0.03mL, 0.5mmol), 65 DEG C are heated to reflux 3h.Add water 15mL, dichloromethane Alkane 15mL adjusts pH to 9~10, liquid separation with 3N NaOH aqueous solution, and water layer extracts (5mL) with methylene chloride, merges methylene chloride Layer is washed (20mL × 2), and saturated common salt washing is spin-dried for obtaining yellow solid 0.63g.FLASH pillar layer separation obtains 0.16g product, Yield 23.2%, TLC content 85%.MS(ESI⁺,m/e):693.45[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 6.95 (1H, pyrroles 5), 6.66 (1H, pyrroles 3), 6.27 (1H, pyrroles Cough up 4), 5.53 (1H, pyrroles 1)

¹³CNMR(400MHz,CDCl₃) δ (ppm): 205.62 (3-C=O), 179.32 (1-C=O), 167.29,169.42 (9- azine), 122.90 (pyrroles 2), 111.97 (pyrroles 5), 103.92-109.8 (pyrroles 3,4)

Embodiment 37 3- descladinosylation -3- oxo -9- (2- pyridine ethane -1- subunit) hydrazone clarithromycin (SIPI8395) preparation

3- descladinosylation -3- oxo -9- hydrazone clarithromycin (0.6g, 1mmol) is dissolved in 5mL methanol, 2- second between addition Acyl pyridine (0.15g, 1.2mmol), glacial acetic acid (0.03mL, 0.5mmol), 65 DEG C are heated to reflux 2.5h.Add water 15mL, dichloro Methane 15mL adjusts pH to 9~10, liquid separation with 3N NaOH aqueous solution, and water layer extracts (5mL) with methylene chloride, merges dichloromethane Alkane layer is washed (20mL × 2), and saturated common salt washing is spin-dried for obtaining yellow solid 0.62g.FLASH separates to obtain product 0.42g, yield 60.0%, HPLC content 92.0%.MS(ESI⁺,m/e):705.28[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 8.65 (1H, pyridines 6), 8.18 (1H, pyridines 3), 7.73 (1H, pyrroles Cough up 4), 7.32 (1H, pyridines 5)

¹³CNMR(400MHz,CDCl₃) δ (ppm): 205.69 (3-C=O), 178.26 (1-C=O), 148.69,169.44 (9- azine), 156.08 (pyridines 2), 136.06 (pyridines 6), 120.84-123.97 (pyridine 3,4,5)

The preparation of 38 3- descladinosylation -3- hydroxyl -9- hydrazone clarithromycin (SIPI8903) of embodiment

9- hydrazone clarithromycin (5.1g, 2mmol) is dissolved in 10mL1N aqueous hydrochloric acid solution, 25 DEG C of stirring 4h.Dichloromethane is added Alkane 10mL adjusts pH to 9-10, liquid separation with 3N sodium hydroxide, and water layer is extracted with 5mL methylene chloride, merges dichloromethane layer, 10mL washing is spin-dried for obtaining crude product 3.8, yield 94.7% after saturated sodium-chloride is dry.

Embodiment 39 3- descladinosylation -3- hydroxyl -9- (4- methoxybenzene ethylidene hydrazone) clarithromycin (SIPI8905) Preparation

3- descladinosylation -3- hydroxyl -9- hydrazone clarithromycin (1.2g, 2mmol) is dissolved in 10mL methanol, is added to methoxy Benzoylformaldoxime (0.9g, 6mmol) and glacial acetic acid (0.34mL, 6mmol), 65 DEG C are heated to reflux 6h, and reaction solution is evaporated, FLASH column Chromatography obtains product 0.7g (yield 47.6%, HPLC purity 86%).MS(ESI⁺,m/e):736.95[M+H]⁺

Embodiment 40 3- descladinosylation -3-O- (4- fluorobenzene acetyl group) -9- (4- methoxybenzene ethylidene hydrazone) carat is mould The preparation of plain (SIPI8501)

3- descladinosylation -3- hydroxyl -9- (4- methoxybenzene ethylidene hydrazone) clarithromycin (1.92g, 2.46mmol) is molten In 10mL methylene chloride, it is added para-fluorophenylacetic acid (1.14g, 7.38mmol), EDCI (1.41g, 7.38mmol), DMAP (0.03g, 0.1mmol), 25 DEG C are stirred at room temperature 6h, adjust pH to 9-10, liquid separation, water layer 5mL dichloromethane with 3N sodium hydroxide Alkane extracting, merges dichloromethane layer, and 10mL washing is spin-dried for after saturated sodium-chloride is dry.65 DEG C of 10mL methanol heating are added in crude product Flow back 2h.FLASH column chromatography for separation obtains product 0.36g.(yield 16.8%, HPLC purity 93.6%).

MS(ESI⁺,m/e):872.63[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.86-7.89 (d, J=12Hz, 2H, 9- phenyl ring 2,6-H), 7.25- 7.38 (m, J=52Hz, 4H, 3- phenyl ring 2,6-H, 9- phenyl ring 3,5-H), 7.06-7.10 (t, J=16Hz, 2H, 3- phenyl ring 3,5- ), H 3.84 (s, 3H, 9- phenyl ring 4-OCHH3), 3.68-3.70 (d, J=9.2Hz, 2H, 3-COCH₂-),2.99(s,3H,6- OCH₃), 2.32 (s, 3H, 9-N=C-CH₃),2.30(s,6H,3’-N(CH₃)₂), 0.81-0.85 (t, J=12Hz, 3H, 13- CH₂CH₃)

¹³CNMR(400M,CDCl₃) δ (ppm): 179.1 (1-CO), 173.6 (3-CO), 171.2 (9-N=C-), 161.2 (9-C=N-), 160.5 (9- phenyl ring 4-C), 131.6 (9- phenyl ring 1-C), 128.7 (9- phenyl ring 2,6-C), 114.0,55.6 (9- Phenyl ring OCH₃), 14.9 (9-C=N-CH₃ ), 163.6 (3- phenyl ring 4-C), 160.5 (3- phenyl ring 1-C), 131.0,129.4 (3- benzene Ring 2,6-C), 115.8,115.6 (3- phenyl ring, 3,5-C), 103.4 (1 '-CH), 50.7 (6-OCH₃),40.9(3-CH₂-)

Embodiment 41 3- descladinosylation -3-O- (4- chloro acetyl) -9- (4- methoxybenzene ethylidene hydrazone) carat is mould The preparation of plain (SIPI8502)

3- descladinosylation -3- hydroxyl -9- (4- methoxybenzene ethylidene hydrazone) clarithromycin (1.1g, 1.49mmol) is dissolved in In 10mL methylene chloride, it is added 4-Chlorophenylacetic acid (1.02,5.98mmol), EDCI (1.15g, 5.98mmol), DMAP (0.02g, 0.1mmol), 6h being stirred at room temperature for 25 DEG C, adjusts pH to 9-10, liquid separation with 3N sodium hydroxide, water layer is extracted with 5mL methylene chloride, Merge dichloromethane layer, 10mL washing is spin-dried for after saturated sodium-chloride is dry.Crude product is added 65 DEG C of 10mL methanol and is heated to reflux 2h. FLASH column chromatography for separation obtains product 0.61g.(yield 46.0%, HPLC purity 88.0%).

MS(ESI⁺,m/e):888.40[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.84-7.88 (d, J=16Hz, 2H, 9- phenyl ring 2,6-H), 7.31- 7.32 (m, J=4Hz, 4H, 3- phenyl ring 2,3,5,6-H), 6.93-6.97 (d, J=16Hz, 2H, 9- phenyl ring 3,5-H), 3.87 (s, 3H, 9- phenyl ring 4-OCH₃), 3.64 (d, J=9.2Hz, 2H, 3-COCH₂-),2.99(s,3H,6-OCH₃),2.32(s,3H,9-N =C-CH₃),2.30(s,6H,3’-N(CH₃)₂), 0.81-0.85 (t, J=12Hz, 3H, 13-CH₂CH₃)

¹³CNMR(400M,CDCl₃) δ (ppm): 179.1 (1-CO), 173.8 (3-CO), 171.0 (9-N=C-), 161.2 (9-C=N-), 160.4 (9- phenyl ring 4-C), 131.6 (9- phenyl ring 1-C), 128.7 (9- phenyl ring 2,6-C), 114.0,55.5 (9- Phenyl ring OCH₃), 14.9 (9-C=N-CH₃ ), 133.5 (3- phenyl ring 4-C), 132.4 (3- phenyl ring 1-C), 131.0 (3- phenyl ring 2,6- ), C 128.9 (3- phenyl ring, 3,5-C), 103.4 (1 '-CH), 50.6 (6-OCH₃),41.0(3-CH₂-)

Embodiment 42 3- descladinosylation -3-O- (4- methoxybenzene acetyl group) -9- (4- methoxybenzene ethylidene hydrazone) gram Draw the preparation of mycin (SIPI8503)

3- descladinosylation -3- hydroxyl -9- (4- methoxybenzene ethylidene hydrazone) clarithromycin (1.1g, 1.49mmol) is dissolved in In 10mL methylene chloride, it is added homoanisic acid (1.02g, 5.98mmol), EDCI (1.15g, 5.98mmol), DMAP (0.02g, 0.1mmol), 25 DEG C are stirred at room temperature 6h, adjust pH to 9-10, liquid separation, water layer 5mL dichloromethane with 3N sodium hydroxide Alkane extracting, merges dichloromethane layer, and 10mL washing is spin-dried for after saturated sodium-chloride is dry.65 DEG C of 10mL methanol heating are added in crude product Flow back 2h.FLASH column chromatography for separation obtains product 0.41g.(yield 31.1%, HPLC purity 91.9%).MS(ESI⁺,m/e): 884.39[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.83-7.85 (d, J=8Hz, 2H, 9- phenyl ring 2,6-H), 7.23-7.25 (d, J=8Hz, 2H, 9- phenyl ring 3,5-H), 6.90-6.92 (d, J=8Hz, 2H, 3- phenyl ring 2,6-H), 6.83-6.85 (d, J= 8Hz, 2H, 3- phenyl ring 3,5-H), 3.84 (s, 3H, 9- phenyl ring 4-OCH₃), 3.78 (s, 3H, 3- phenyl ring 4-OCH₃),3.61-3.63 (d, J=8Hz, 2H, 3-COCH ₂-),2.96(s,3H,6-OCH₃), 2.29 (s, 3H, 9-N=C-CH₃),2.27(s,6H,3’-N (CH₃)₂), 0.80-0.84 (t, J=16Hz, 3H, 13-CH₂CH₃)

¹³CNMR(400M,CDCl₃) δ (ppm): 178.9 (1-CO), 173.4 (3-CO), 171.4 (9-N=C-), 160.9 (9-C=N-), 160.1 (9- phenyl ring 4-C), 131.46 (9- phenyl ring 1-C), 128.0 (9- phenyl ring 2,6-C), 113.6,55.5 (9- Phenyl ring OCH₃), 14.6 (9-C=N-CH₃ ), 158.8 (3- phenyl ring 4-C), 130.4 (3- phenyl ring 2,6-C), 125.7 (3- phenyl ring 1- ), C 114.0 (3- phenyl ring, 3,5-C), 55.2 (3-O-CH₃),103.2(1’-CH),50.4(6-OCH₃),40.7(3-CH₂-)

Embodiment 43 3- descladinosylation -3- hydroxyl -9- (4- fluorobenzene ethylidene hydrazone) clarithromycin

3- descladinosylation -3- hydroxyl -9- hydrazone clarithromycin (4.0g, 6.68mmol) is dissolved in 10mL methanol, addition pair Fluoro acetophenone (2.77g, 20.04mmol) and glacial acetic acid (1.15mL, 20.04mmol), 65 DEG C are heated to reflux 6h, and reaction solution steams Dry, FLASH column chromatography for separation obtains product 3.65g (yield 75.5%).MS(ESI⁺,m/e):724.91[M+H]⁺

Embodiment 44 3- descladinosylation -3-O- (4- fluorobenzene acetyl group) -9- (4- fluorobenzene ethylidene hydrazone) clarithromycin (SIPI8504) preparation

3- descladinosylation -3- hydroxyl -9- (4- fluorobenzene ethylidene hydrazone) clarithromycin (1.74g, 2.30mmol) is dissolved in In 10mL methylene chloride, it is added para-fluorophenylacetic acid (1.47g, 9.2mmol), EDCI (1.77g, 9.2mmol), DMAP (0.03g, 0.1mmol), 25 DEG C of stirring 6h adjust pH to 9-10, liquid separation with 3N sodium hydroxide, and water layer is extracted with 5mL methylene chloride, is merged Dichloromethane layer, 10mL washing are spin-dried for after saturated sodium-chloride is dry.Crude product is added 65 DEG C of 10mL methanol and is heated to reflux 2h.FLASH Column chromatography for separation obtains product 0.76g.Yield 36.7%, HPLC purity 97.8%.

MS(ESI⁺,m/e):860.26[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.85-7.88 (m, J=12Hz, 2H, 9- phenyl ring 2,6-H), 7.29- 7.32 (m, J=12Hz, 2H, 9- phenyl ring 3,5-H), 7.05-7.09 (t, J=12Hz, 2H, 3- phenyl ring 2,6-H), 6.98-7.01 (t, J=12Hz, 2H, 3- phenyl ring 3,5-H), 3.64-3.66 (d, J=8Hz, 2H, 3-COCH ₂-),2.96(s,3H,6-OCH₃), 2.30 (s, 3H, 9-N=C-CH₃),2.27(s,6H,3’-N(CH₃)₂), 0.80-0.84 (t, J=16Hz, 3H, 13-CH₂CH₃)

¹³CNMR(400M,CDCl₃) δ (ppm): 179.5 (1-CO), 173.5 (3-CO), 170.9 (9-N=C-), 159.5 (9-C=N-), 165.1 (9- phenyl ring 4-C), 162.6 (9- phenyl ring 1-C), 134.9,128.5 (9- phenyl ring 2,6-C), 115.4, 115.2 (9- phenyl ring 3,5-C), 14.8 (9-C=N-CH₃ ), 163.4 (3- phenyl ring 4-C), 160.9 (3- phenyl ring 1-C), 131.0, 129.4 (3- phenyl ring 2,6-C), 115.5,115.3 (3- phenyl ring, 3,5-C), 103.4 (1 '-CH), 50.4 (6-OCH₃),40.7 (3-CH₂-)

Embodiment 45 3- descladinosylation -3-O- (4- chloro acetyl) -9- (4- fluorobenzene ethylidene hydrazone) clarithromycin (SIPI8505)

3- descladinosylation -3- hydroxyl -9- (4- fluorobenzene ethylidene hydrazone) clarithromycin (1.74g, 2.30mmol) is dissolved in In 10mL methylene chloride, it is added 4-Chlorophenylacetic acid (1.57g, 9.2mmol), EDCI (1.77g, 9.2mmol), DMAP (0.03g, 0.1mmol), 25 DEG C of stirring 6h adjust pH to 9-10, liquid separation with 3N sodium hydroxide, and water layer is extracted with 5mL methylene chloride, is merged Dichloromethane layer, 10mL washing are spin-dried for after saturated sodium-chloride is dry.Crude product is added 65 DEG C of 10mL methanol and is heated to reflux 2h.FLASH Column chromatography for separation obtains product 0.82g (yield 38.9%, HPLC purity 97.9%).

MS(ESI⁺,m/e):876.33[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.85-7.89 (m, J=16Hz, 2H, 9- phenyl ring 2,6-H), 7.29 (s, 4H, 3- phenyl ring 2,3,5,6-H), 7.05-7.09 (t, J=16Hz, 2H, 9- phenyl ring 3,5-H), 3.65-3.67 (d, J=8Hz, 2H,3-COCH2-),2.98(s,3H,6-OCH₃), 2.30 (s, 3H, 9-N=C-CH₃),2.27(s,6H,3’-N(CH₃)₂), 0.81-0.85 (t, J=16Hz, 3H, 13-CH₂CH₃)

¹³CNMR(400M,CDCl₃) δ (ppm): 179.4 (1-CO), 173.4 (3-CO), 170.7 (9-N=C-), 159.5 (9-C=N-), 165.0 (9- phenyl ring 4-C), 162.6 (9- phenyl ring 1-C), 134.9,128.5 (9- phenyl ring 2,6-C), 115.3, 115.1 (9- phenyl ring 3,5-C), 14.8 (9-C=N-CH₃ ), 133.3 (3- phenyl ring 4-C), 132.3 (3- phenyl ring 1-C), 130.8 (3- phenyl ring 2,6-C), 128.7 (3- phenyl ring, 3,5-C), 103.4 (1 '-CH), 50.4 (6-OCH₃),40.7(3-CH₂-)

Embodiment 46 3- descladinosylation -3-O- (4- methoxybenzene acetyl group) -9- (4- fluorobenzene ethylidene hydrazone) carat is mould The preparation of plain (SIPI8506)

3- descladinosylation -3- hydroxyl -9- (4- fluorobenzene ethylidene hydrazone) clarithromycin (1.82g, 2.51mmol) is dissolved in In 10mL methylene chloride, it is added homoanisic acid (1.67g, 10.05mmol), EDCI (1.93g, 10.05mmol), DMAP (0.03g, 0.1mmol), 25 DEG C of stirring 6h adjust pH to 9-10, liquid separation with 3N sodium hydroxide, and water layer is taken out with 5mL methylene chloride It mentions, merges dichloromethane layer, 10mL washing is spin-dried for after saturated sodium-chloride is dry.Crude product is added 65 DEG C of 10mL methanol and is heated to reflux 2h.FLASH column chromatography for separation obtains product 0.89g (yield 44.5%, HPLC purity 97.5%).

MS(ESI⁺,m/e):872.46[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.85-7.88 (q, J=12Hz, 2H, 9- phenyl ring 2,6-H), 7.24- 7.26 (d, J=8Hz, 2H, 3- phenyl ring 2,6-H), 7.04-7.09 (t, J=20Hz, 2H, 9- phenyl ring 3,5-H), 6.83-6.86 (t, J=12Hz, 2H, 3- phenyl ring 3,5-H), 3.78 (s, 3H, 3- phenyl ring 4-OCH₃), 3.61-3.63 (d, J=8Hz, 2H, 3- COCH ₂-),2.97(s,3H,6-OCH₃), 2.30 (s, 3H, 9-N=C-CH₃),2.27(s,6H,3’-N(CH₃)₂),0.80-0.84 (t, J=16Hz, 3H, 13-CH₂CH₃)

¹³CNMR(400M,CDCl₃) δ (ppm): 179.5 (1-CO), 173.5 (3-CO), 171.4 (9-N=C-), 159.5 (9-C=N-), 165.0 (9- phenyl ring 4-C), 162.6 (9- phenyl ring 1-C), 134.9,128.5 (9- phenyl ring 2,6-C), 115.3, 115.1 (9- phenyl ring 3,5-C), 14.8 (9-C=N-CH₃ ), 158.9 (3- phenyl ring 4-C), 125.7 (3- phenyl ring 1-C), 130.5 (3- phenyl ring 2,6-C), 114.0 (3- phenyl ring, 3,5-C), 55.2 (3-O-CH₃),103.2(1’-CH),50.4(6-OCH₃),40.7 (3-CH₂-)

Embodiment 47 3- descladinosylation -3-O- (4- phenylacetyl group) -9- (4- fluorobenzene ethylidene hydrazone) clarithromycin (SIPI8507)

3- descladinosylation -3- hydroxyl -9- (4- fluorobenzene ethylidene hydrazone) clarithromycin (1.74g, 2.30mmol) is dissolved in In 10mL methylene chloride, it is added phenylacetic acid (1.37g, 10.05mmol), EDCI (1.67g, 10.05mmol), DMAP (0.03g, 0.1mmol), 25 DEG C of stirring 6h adjust pH to 9-10, liquid separation with 3N sodium hydroxide, and water layer is extracted with 5mL methylene chloride, is merged Dichloromethane layer, 10mL washing are spin-dried for after saturated sodium-chloride is dry.Crude product is added 65 DEG C of 10mL methanol and is heated to reflux 2h.FLASH Column chromatography for separation obtains product 1.06g (yield 50.1%, HPLC purity 98.9%).

MS(ESI⁺,m/e):842.56[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.85-7.89 (m, J=16Hz, 2H, 9- phenyl ring 2,6-H), 7.30- 7.39 (m, J=36Hz, 5H, 3- phenyl ring 2,3,4,5,6-H), 7.06-7.10 (t, J=16Hz, 2H, 9- phenyl ring 3,5-H), 3.68-3.70 (d, J=8Hz, 2H, 3-COCH ₂-),2.98(s,3H,6-OCH₃), 2.30 (s, 3H, 9-N=C-CH₃),2.28 (s,6H,3’-N(CH₃)₂), 0.81-0.85 (t, J=16Hz, 3H, 13-CH₂CH₃)

¹³CNMR(400M,CDCl₃) δ (ppm): 179.5 (1-CO), 173.5 (3-CO), 171.1 (9-N=C-), 159.5 (9-C=N-), 165.1 (9- phenyl ring 4-C), 162.6 (9- phenyl ring 1-C), 134.9,128.5 (9- phenyl ring 2,6-C), 115.4, 115.2 (9- phenyl ring 3,5-C), 14.8 (9-C=N-CH₃ ), 133.9 (3- phenyl ring 4-C), 129.5 (3- phenyl ring 2,3,5,6-C), 127.3 (3- phenyl ring 4-C), 103.3 (1 '-CH), 50.4 (6-OCH₃),41.6(3-CH₂-)

Embodiment 48 3- descladinosylation -3- hydroxyl -9- (4- chlorobenzene ethylidene hydrazone) clarithromycin

3- descladinosylation -3- hydroxyl -9- hydrazone clarithromycin (7.87g, 13.05mmol) is dissolved in 30mL methanol, is added Parachloroacetophenone (6.05g, 39.15mmol) and glacial acetic acid (2.24mL, 39.15mmol), 65 DEG C are heated to reflux 6h, and reaction solution steams Dry, FLASH column chromatography for separation obtains product 6.68g (yield 67.5%).MS(ESI⁺,m/e):741.37[M+H]⁺

Embodiment 49 3- descladinosylation -3-O- (4- fluorobenzene acetyl group) -9- (4- chlorobenzene ethylidene hydrazone) clarithromycin (SIPI8508) preparation

3- descladinosylation -3- hydroxyl -9- (4- chlorobenzene ethylidene hydrazone) clarithromycin (1.67g, 2.26mmol) is dissolved in In 10mL methylene chloride, it is added para-fluorophenylacetic acid (1.39g, 9.02mmol), EDCI (1.73g, 9.02mmol), DMAP (0.03g, 0.1mmol), 25 DEG C of stirring 6h adjust pH to 9-10, liquid separation with 3N sodium hydroxide, and water layer is taken out with 5mL methylene chloride It mentions, merges dichloromethane layer, 10mL washing is spin-dried for after saturated sodium-chloride is dry.Crude product is added 65 DEG C of 10mL methanol and is heated to reflux 2h.FLASH column chromatography for separation obtains product 1.25g (yield 63.0%, HPLC purity 98.1%).

MS(ESI⁺,m/e):876.31[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.80-7.82 (d, J=8Hz, 2H, 9- phenyl ring 2,6-H), 7.35-7.37 (d, J=8Hz, 2H, 9- phenyl ring 3,5-H), 7.29-7.32 (q, J=12Hz, 2H, 3- phenyl ring 2,6-H), 6.98-7.02 (t, J= 12Hz, 2H, 3- phenyl ring 3,5-H), 3.65-3.67 (d, J=8Hz, 2H, 3-COCH ₂-),2.97(s,3H,6-OCH₃),2.30(s, 3H, 9-N=C-CH₃),2.27(s,6H,3’-N(CH₃)₂), 0.80-0.84 (t, J=16Hz, 3H, 13-CH₂CH₃)

¹³CNMR(400M,CDCl₃) δ (ppm): 179.5 (1-CO), 173.4 (3-CO), 171.0 (9-N=C-), 159.5 (9-C=N-), 137.1 (9- phenyl ring 4-C), 135.7 (9- phenyl ring 1-C), 128.5 (9- phenyl ring 2,6-C), 127.9 (9- phenyl ring 3, 5-C), 14.7 (9-C=N-CH₃ ),

163.4 (3- phenyl ring 4-C), 160.9 (3- phenyl ring 1-C), 131.0,129.4 (3- phenyl ring 2,6-C), 115.5, 115.3 (3- phenyl ring, 3,5-C), 103.4 (1 '-CH), 50.4 (6-OCH₃),40.7(3-CH₂-)

Embodiment 50 3- descladinosylation -3-O- (4- chloro acetyl) -9- (4- chlorobenzene ethylidene hydrazone) clarithromycin (SIPI8509) preparation

3- descladinosylation -3- hydroxyl -9- (4- chlorobenzene ethylidene hydrazone) clarithromycin (1.67g, 2.26mmol) is dissolved in In 10mL methylene chloride, it is added 4-Chlorophenylacetic acid (1.54g, 9.02mmol), EDCI (1.73g, 9.02mmol), DMAP (0.03g, 0.1mmol), 25 DEG C of stirring 6h adjust pH to 9-10, liquid separation with 3N sodium hydroxide, and water layer is taken out with 5mL methylene chloride It mentions, merges dichloromethane layer, 10mL washing is spin-dried for after saturated sodium-chloride is dry.Crude product is added 65 DEG C of 10mL methanol and is heated to reflux 2h.FLASH column chromatography for separation obtains product 1.43g (yield 70.7%, HPLC purity 98.1%).

MS(ESI⁺,m/e):892.33[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.80-7.82 (d, J=8Hz, 2H, 9- phenyl ring 2,6-H), 7.35-7.37 (d, J=8Hz, 2H, 9- phenyl ring 3,5-H), 7.28 (s, 4H, 3- phenyl ring 2,3,5,6-H), 3.64-3.66 (d, J=8Hz, 2H, 3- COCH ₂-),2.96(s,3H,6-OCH₃), 2.29 (s, 3H, 9-N=C-CH₃),2.26(s,6H,3’-N(CH₃)₂),0.80-0.84 (t, J=16Hz, 3H, 13-CH₂CH₃)

¹³CNMR(400M,CDCl₃) δ (ppm): 179.6 (1-CO), 173.4 (3-CO), 171.7 (9-N=C-), 159.5 (9-C=N-), 137.1 (9- phenyl ring 4-C), 135.7 (9- phenyl ring 1-C), 128.5 (9- phenyl ring 2,6-C), 127.6 (9- phenyl ring 3, 5-C), 14.7 (9-C=N-CH₃ ), 133.3 (3- phenyl ring 4-C), 132.2 (3- phenyl ring 1-C), 130.8 (3- phenyl ring 2,6-C), 128.7 (3- phenyl ring, 3,5-C), 103.4 (1 '-CH), 50.4 (6-OCH₃),40.8(3-CH₂-)

Embodiment 51 3- descladinosylation -3-O- (4- methoxybenzene acetyl group) -9- (4- chlorobenzene ethylidene hydrazone) carat is mould The preparation of plain (SIPI8510)

3- descladinosylation -3- hydroxyl -9- (4- chlorobenzene ethylidene hydrazone) clarithromycin (1.67g, 2.26mmol) is dissolved in In 10mL methylene chloride, it is added homoanisic acid (1.50g, 9.02mmol), EDCI (1.73g, 9.02mmol), DMAP (0.03g, 0.1mmol), 25 DEG C of stirring 6h adjust pH to 9-10, liquid separation with 3N sodium hydroxide, and water layer is taken out with 5mL methylene chloride It mentions, merges dichloromethane layer, 10mL washing is spin-dried for after saturated sodium-chloride is dry.Crude product is added 65 DEG C of 10mL methanol and is heated to reflux 2h.FLASH column chromatography for separation obtains product 0.36g (yield 17.9%, HPLC purity 96.6%).

MS(ESI⁺,m/e):888.35[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.80-7.82 (d, J=8Hz, 2H, 9- phenyl ring 2,6-H), 7.35-7.37 (d, J=8Hz, 2H, 9- phenyl ring 3,5-H), 7.24-7.26 (d, J=8Hz, 2H, 3- phenyl ring 2,6-H), 6.84-6.86 (d, J= 8Hz, 2H, 3- phenyl ring 3,5-H), 3.79 (s, 3H, 3- phenyl ring 4-OCH₃), 3.61-3.63 (d, J=8Hz, 2H, 3-COCH ₂-), 2.97(s,3H,6-OCH₃), 2.30 (s, 3H, 9-N=C-CH₃),2.28(s,6H,3’-N(CH₃)₂), 0.81-0.85 (t, J= 16Hz,3H,13-CH₂CH₃)

¹³CNMR (400M, CDCl3) δ (ppm): 179.6 (1-CO), 173.5 (3-CO), 171.5 (9-N=C-), 159.5 (9-C=N-), 137.2 (9- phenyl ring 4-C), 135.7 (9- phenyl ring 1-C), 128.6 (9- phenyl ring 2,6-C), 127.9 (9- phenyl ring 3, 5-C), 14.7 (9-C=N-CH₃ ), 159.0 (3- phenyl ring 4-C), 125.8 (3- phenyl ring 1-C), 130.5 (3- phenyl ring 2,6-C), 114.1 (3- phenyl ring, 3,5-C), 55.3 (3-O-CH₃),103.2(1’-CH),50.4(6-OCH₃),40.7(3-CH₂-)

Embodiment 52 3- descladinosylation -3-O- (4- phenylacetyl group) -9- (4- chlorobenzene ethylidene hydrazone) clarithromycin (SIPI8511) preparation

3- descladinosylation -3- hydroxyl -9- (4- chlorobenzene ethylidene hydrazone) clarithromycin (1.67g, 2.26mmol) is dissolved in In 10mL methylene chloride, it is added phenylacetic acid (1.23g, 9.02mmol), EDCI (1.73g, 9.02mmol), DMAP (0.03g, 0.1mmol), 25 DEG C of stirring 6h adjust pH to 9-10, liquid separation with 3N sodium hydroxide, and water layer is extracted with 5mL methylene chloride, is merged Dichloromethane layer, 10mL washing are spin-dried for after saturated sodium-chloride is dry.Crude product is added 65 DEG C of 10mL methanol and is heated to reflux 2h.FLASH Column chromatography for separation obtains product 0.3g (yield 15.4%, HPLC purity 97.0%).

MS(ESI⁺,m/e):858.53[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.80-7.82 (d, J=8Hz, 2H, 9- phenyl ring 2,6-H), 7.36-7.38 (d, J=8Hz, 2H, 9- phenyl ring 3,5-H), 7.26-7.33 (m, J=28Hz, 5H, 3- phenyl ring 2,3,4,5,6-H), 3.68-3.70 (d, J=8Hz, 2H, 3-COCH ₂-),2.97(s,3H,6-OCH₃), 2.30 (s, 3H, 9-N=C-CH₃),2.28(s,6H,3’-N (CH₃)₂), 0.81-0.85 (t, J=16Hz, 3H, 13-CH₂CH₃)

¹³CNMR (400M, CDCl3) δ (ppm): 179.6 (1-CO), 173.5 (3-CO), 171.1 (9-N=C-), 159.5 (9-C=N-), 137.2 (9- phenyl ring 4-C), 135.7 (9- phenyl ring 1-C), 128.6 (9- phenyl ring 2,6-C), 127.9 (9- phenyl ring 3, 5-C), 14.7 (9-C=N-CH₃ ), 133.7 (3- phenyl ring 4-C), 129.5 (3- phenyl ring 2,3,5,6-C), 127.3 (3- phenyl ring 4- C),103.3(1’-CH),50.4(6-OCH₃),41.6(3-CH₂-)

The preparation of 53 3- descladinosylation -3- hydroxyl -9- of embodiment (1- (pyrroles -2- base) ethylidene hydrazone) clarithromycin

3- descladinosylation -3- hydroxyl -9- hydrazone clarithromycin (6.0g, 9.32mmol) is dissolved in 20mL methanol, and 2- is added Acetyl pyrrole (2.03g, 18.64mmol) and glacial acetic acid (1.60mL, 27.96mmol), 65 DEG C are heated to reflux 6h, and reaction solution steams Dry, FLASH column chromatography for separation obtains product 5.34g.(yield 77.3%, HPLC purity 89.5%).

MS(ESI⁺,m/e):695.45[M+H]⁺

Embodiment 54 3- descladinosylation -3-O- (4- fluorobenzene acetyl group) -9- (1- (pyrroles -2- base) ethylidene hydrazone) gram Draw the preparation of mycin (SIPI8512)

3- descladinosylation -3- hydroxyl -9- (1- (pyrroles -2- base) ethylidene hydrazone) clarithromycin (1.00g, 1.44mmol) It is dissolved in 10mL methylene chloride, is added para-fluorophenylacetic acid (0.66g, 4.32mmol), EDCI (1.11g, 5.76mmol), DMAP (0.02g, 0.1mmol), 25 DEG C of stirring 6h adjust pH to 9-10, liquid separation with 3N sodium hydroxide, and water layer is taken out with 5mL methylene chloride It mentions, merges dichloromethane layer, 10mL washing is spin-dried for after saturated sodium-chloride is dry.Crude product is added 65 DEG C of 10mL methanol and is heated to reflux 2h.FLASH column chromatography for separation obtains product 0.48g (yield 40.1%, HPLC purity 90.6%).

MS(ESI⁺,m/e):831.44[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 9.18 (s, 1H, 9- pyrroles N-H), 7.29-7.32 (q, 2H, J=12Hz, 3- phenyl ring 2,6-H), 6.98-7.02 (t, J=12Hz, 2H, 3- phenyl ring 3,5-H), 6.89 (s, 1H, 9- pyrroles 5-H), 6.59 (s, 1H, 9- pyrroles 3-H), 6.24-6.25 (d, 1H, J=4Hz, 9- pyrroles 4-H), 3.64-3.66 (d, J=8Hz, 2H, 3- COCH ₂-),2.93(s,3H,6-OCH₃),2.27(s,6H,3’-N(CH₃)₂), 2.24 (s, 3H, 9-N=C-CH₃),0.80-0.84 (t, J=16Hz, 3H, 13-CH₂CH₃)

¹³CNMR (400M, CDCl3) δ (ppm): 179.3 (1-CO), 173.4 (3-CO), 171.0 (9-N=C-), 154.6 (9-C=N-), 131.4 (9- pyrroles 2-C), 121.0 (9- pyrroles 5-C), 111.8 (9- pyrroles 3-C), 109.8 (9- pyrroles 4- ), C 14.4 (9-C=N-CH₃ ), 163.4 (3- phenyl ring 4-C), 160.9 (3- phenyl ring 1-C), 131.0,129.5 (3- phenyl ring 2,6- ), C 115.5,115.3 (3- phenyl ring, 3,5-C), 103.5 (1 '-CH), 50.3 (6-OCH₃),40.7(3-CH₂-)

Embodiment 55 3- descladinosylation -3-O- (4- chloro acetyl) -9- (1- (pyrroles -2- base) ethylidene hydrazone) gram Draw the preparation of mycin (SIPI8513)

3- descladinosylation -3- hydroxyl -9- (1- (pyrroles -2- base) ethylidene hydrazone) clarithromycin (1.00g, 1.44mmol) It is dissolved in 10mL methylene chloride, is added 4-Chlorophenylacetic acid (0.98g, 5.76mmol), EDCI (1.11g, 5.76mmol), DMAP (0.02g, 0.1mmol), 25 DEG C of stirring 6h adjust pH to 9-10, liquid separation with 3N sodium hydroxide, and water layer is taken out with 5mL methylene chloride It mentions, merges dichloromethane layer, 10mL washing is spin-dried for after saturated sodium-chloride is dry.Crude product is added 65 DEG C of 10mL methanol and is heated to reflux 2h.FLASH column chromatography for separation obtains product 0.48g (yield 39.4%, HPLC purity 90.1%).

MS(ESI⁺,m/e):847.19[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 9.18 (s, 1H, 9- pyrroles N-H), 7.28 (s, 4H, 3- phenyl ring 2,3,5, 6-H), 6.89 (s, 1H, 9- pyrroles 5-H), 6.59 (s, 1H, 9- pyrroles 3-H), 6.24-6.25 (d, J=4Hz, 1H, 9- pyrroles 4- H),2.93(s,3H,6-OCH₃), 3.677-3.70 (d, J=12Hz, 2H, 3-COCH ₂-),2.27(s,6H,3’-N(CH₃)₂), 2.24 (s, 3H, 9-N=C-CH₃), 0.80-0.84 (t, J=16Hz, 3H, 13-CH₂CH₃)

¹³CNMR (400M, CDCl3) δ (ppm): 179.3 (1-CO), 173.4 (3-CO), 171.0 (9-N=C-), 154.6 (9-C=N-), 131.4 (9- pyrroles 2-C), 121.0 (9- pyrroles 5-C), 111.8 (9- pyrroles 3-C), 109.8 (9- pyrroles 4- ), C 14.4 (9-C=N-CH₃ ), 133.3 (3- phenyl ring 4-C), 132.2 (3- phenyl ring 1-C), 130.8 (3- phenyl ring 2,6-C), 128.7 (3- phenyl ring, 3,5-C), 103.6 (1 '-CH), 50.4 (6-OCH₃),40.8(3-CH₂-)

Embodiment 56 3- descladinosylation -3-O- (4- methoxybenzene acetyl group) -9- (1- (pyrroles -2- base) ethylidene Hydrazone) clarithromycin (SIPI8514) preparation

3- descladinosylation -3- hydroxyl -9- (1- (pyrroles -2- base) ethylidene hydrazone) clarithromycin (1.00g, 1.44mmol) It is dissolved in 10mL methylene chloride, is added homoanisic acid (0.72g, 4.32mmol), EDCI (1.11g, 5.76mmol), DMAP (0.02g, 0.1mmol), 25 DEG C of stirring 6h adjust pH to 9-10, liquid separation, water layer 5mL dichloromethane with 3N sodium hydroxide Alkane extracting, merges dichloromethane layer, and 10mL washing is spin-dried for after saturated sodium-chloride is dry.65 DEG C of 10mL methanol heating are added in crude product Flow back 2h.FLASH column chromatography for separation obtains product 0.63g (yield 51.9%, HPLC purity 88.7%).

MS(ESI⁺,m/e):843.58[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 9.18 (s, 1H, 9- pyrroles N-H), 7.24-7.26 (d, J=8Hz, 2H, 3- phenyl ring 2,6-H), 6.84-6.86 (d, J=8Hz, 2H, 3- phenyl ring 3,5-H), 6.89 (s, 1H, 9- pyrroles 5-H), 6.59 (s, 1H, 9- pyrroles 3-H), 6.24-6.26 (d, J=8Hz, 1H, 9- pyrroles 4-H), 3.79 (s, 3H, 3- phenyl ring 4-OCH₃),3.61- 3.63 (d, J=8Hz, 2H, 3-COCH ₂-),2.93(s,3H,6-OCH₃),2.28(s,6H,3’-N(CH₃)₂),2.24(s,3H, 9-N=C-CH₃), 0.81-0.85 (t, J=16Hz, 3H, 13-CH₂CH₃)

¹³CNMR (400M, CDCl3) δ (ppm): 179.4 (1-CO), 173.5 (3-CO), 171.4 (9-N=C-), 154.5 (9-C=N-), 131.4 (9- pyrroles 2-C), 121.0 (9- pyrroles 5-C), 111.7 (9- pyrroles 3-C), 109.7 (9- pyrroles 4- ), C 14.4 (9-C=N-CH₃ ), 158.9 (3- phenyl ring 4-C), 130.5 (3- phenyl ring 2,6-C), 125.7 (3- phenyl ring 1-C), 114.0 (3- phenyl ring, 3,5-C), 55.3 (3-O-CH₃),103.3(1’-CH),50.4(6-OCH₃),40.7(3-CH₂-)

57 3- descladinosylation -3-O- acetyl group -9- of embodiment (1- (pyrroles -2- base) ethylidene hydrazone) clarithromycin (SIPI8515) preparation

3- descladinosylation -3- hydroxyl -9- (1- (pyrroles -2- base) ethylidene hydrazone) clarithromycin (1.00g, 1.44mmol) It is dissolved in 10mL methylene chloride, is added to acetic anhydride (0.35g, 2.88mmol), EDCI (1.11g, 5.76mmol), DMAP (0.02g, 0.1mmol), 25 DEG C of stirring 6h adjust pH to 9-10, liquid separation with 3N sodium hydroxide, and water layer is taken out with 5mL methylene chloride It mentions, merges dichloromethane layer, 10mL washing is spin-dried for after saturated sodium-chloride is dry.Crude product is added 65 DEG C of 10mL methanol and is heated to reflux 2h.FLASH column chromatography for separation obtains product 0.32g (yield 30.2%, HPLC purity 91.1%).

MS(ESI⁺,m/e):737.40[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 9.18 (s, 1H, 9- pyrroles N-H), 6.84-6.86 (d, J=8Hz, 2H, 3- phenyl ring 3,5-H), 6.89 (s, 1H, 9- pyrroles 5-H), 6.59 (s, 1H, 9- pyrroles 3-H), 6.24-6.26 (d, J=8Hz, 1H, 9- pyrroles 4-H), 3.79 (s, 3H, 3- phenyl ring 4-OCH₃),2.93(s,3H,6-OCH₃),2.28(s,6H,3’-N(CH₃)₂), 2.24 (s, 3H, 9-N=C-CH₃),2.12(s,3H,3-CH₃), 0.81-0.85 (t, J=16Hz, 3H, 13-CH₂CH₃)

¹³CNMR (400M, CDCl3) δ (ppm): 179.4 (1-CO), 173.6 (3-CO), 170.5 (9-N=C-), 154.5 (9-C=N-), 131.4 (9- pyrroles 2-C), 121.0 (9- pyrroles 5-C), 111.7 (9- pyrroles 3-C), 109.7 (9- pyrroles 4- C), 14.4 (9-C=N-CH₃ ),103.3(1’-CH),50.4(6-OCH₃),21.2(3-CH₃)

The preparation of 58 3- descladinosylation -3- hydroxyl -9- of embodiment (1- (furans -2- base) ethylidene hydrazone) clarithromycin

3- descladinosylation -3- hydroxyl -9- hydrazone clarithromycin (8.00g, 13.27mmol) is dissolved in 10mL methanol, is added To 2- acetyl furan (4.38g, 39.80mmol) and glacial acetic acid (2.28mL, 39.80mmol), 65 DEG C are heated to reflux 6h, reaction Liquid is evaporated, and FLASH column chromatography for separation obtains product 7.2g.(yield 78.1%, HPLC purity 90.2%).MS(ESI⁺,m/e): 696.88[M+H]⁺

Embodiment 59 3- descladinosylation -3-O- (4- fluorobenzene acetyl group) -9- (1- (furans -2- base) ethylidene hydrazone) gram Draw the preparation of mycin (SIPI8516)

3- descladinosylation -3- hydroxyl -9- (1- (furans -2- base) ethylidene hydrazone) clarithromycin (1.50g, 2.16mmol) It is dissolved in 10mL methylene chloride, is added para-fluorophenylacetic acid (1.00g, 6.47mmol), EDCI (1.24g, 6.47mmol), DMAP (0.03g, 0.1mmol), 25 DEG C of stirring 6h adjust pH to 9-10, liquid separation with 3N sodium hydroxide, and water layer is taken out with 5mL methylene chloride It mentions, merges dichloromethane layer, 10mL washing is spin-dried for after saturated sodium-chloride is dry.Crude product is added 65 DEG C of 10mL methanol and is heated to reflux 2h.FLASH column chromatography for separation obtains product 0.70g (yield 39.0%, HPLC purity 95.7%).

MS(ESI⁺,m/e):832.54[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.50 (s, 1H, 9- furans 5-H), 7.29-7.32 (q, 2H, J=12Hz, 3- phenyl ring 2,6-H), 6.98-7.02 (t, J=12Hz, 2H, 3- phenyl ring 3,5-H), 6.85-6.86 (d, J=4Hz, 1H, 9- furans 4-H), 6.46-6.47 (m, J=4Hz, 1H, 9- furans 3-H), 3.65-3.67 (d, J=8Hz, 2H, 3-COCH ₂-),2.93(s, 3H,6-OCH₃),2.27(s,6H,3’-N(CH₃)₂), 2.26 (s, 3H, 9-N=C-CH₃), 0.80-0.84 (t, J=16Hz, 3H, 13-CH₂CH₃)

¹³CNMR (400M, CDCl3) δ (ppm): 180.6 (1-CO), 173.5 (3-CO), 171.0 (9-N=C-), 144.0 (9-C=N-), 153.4 (9- furans 2-C), 153.2 (9- furans 5-C), 111.7 (9- furans 3-C), 110.8 (9- furans 4- ), C 14.1 (9-C=N-CH₃ ), 163.4 (3- phenyl ring 4-C), 160.9 (3- phenyl ring 1-C), 131.0,129.5 (3- phenyl ring 2,6- ), C 115.5,115.3 (3- phenyl ring, 3,5-C), 103.5 (1 '-CH), 50.3 (6-OCH₃),40.7(3-CH₂-)

Embodiment 60 3- descladinosylation -3-O- (4- chloro acetyl) -9- (1- (furans -2- base) ethylidene hydrazone) gram Draw the preparation of mycin (SIPI8517)

3- descladinosylation -3- hydroxyl -9- (1- (furans -2- base) ethylidene hydrazone) clarithromycin (1.50g, 2.16mmol) It is dissolved in 10mL methylene chloride, is added 4-Chlorophenylacetic acid (1.11g, 6.47mmol), EDCI (1.24g, 6.47mmol), DMAP (0.03g, 0.1mmol), 25 DEG C of stirring 6h adjust pH to 9-10, liquid separation with 3N sodium hydroxide, and water layer is taken out with 5mL methylene chloride It mentions, merges dichloromethane layer, 10mL washing is spin-dried for after saturated sodium-chloride is dry.Crude product is added 65 DEG C of 10mL methanol and is heated to reflux 2h.FLASH column chromatography for separation obtains product 0..46g (yield 25.2%, HPLC purity 88.0%).

MS(ESI⁺,m/e):848.41[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.50 (s, 1H, 9- furans 5-H), 7.29 (s, 4H, 3- phenyl ring 2,3,5, 6-H), 6.85-6.86 (d, J=4Hz, 1H, 9- furans 4-H), 6.46-6.47 (m, J=4Hz, 1H, 9- furans 3-H), 2.93 (s,3H,6-OCH₃), 3.64-3.66 (d, J=8Hz, 2H, 3-COCH ₂-),2.27(s,6H,3’-N(CH₃)₂),2.26(s,3H, 9-N=C-CH₃), 0.80-0.84 (t, J=16Hz, 3H, 13-CH₂CH₃)

¹³CNMR (400M, CDCl3) δ (ppm): 180.5 (1-CO), 173.4 (3-CO), 170.7 (9-N=C-), 144.0 (9-C=N-), 153.4 (9- furans 2-C), 153.2 (9- furans 5-C), 111.6 (9- furans 3-C), 110.8 (9- furans 4- ), C 13.5 (9-C=N-CH₃ ), 133.3 (3- phenyl ring 4-C), 132.3 (3- phenyl ring 1-C), 130.8 (3- phenyl ring 2,6-C), 128.7 (3- phenyl ring, 3,5-C), 103.5 (1 '-CH), 50.3 (6-OCH₃),40.8(3-CH₂-)

Embodiment 61 3- descladinosylation -3-O- (4- methoxybenzene acetyl group) -9- (1- (furans -2- base) ethylidene Hydrazone) clarithromycin (SIPI8518) preparation

3- descladinosylation -3- hydroxyl -9- (1- (furans -2- base) ethylidene hydrazone) clarithromycin (1.50g, 2.16mmol) It is dissolved in 10mL methylene chloride, is added homoanisic acid (1.08g, 6.47mmol), EDCI (1.24g, 6.47mmol), DMAP (0.03g, 0.1mmol), 25 DEG C of stirring 6h adjust pH to 9-10, liquid separation, water layer 5mL dichloromethane with 3N sodium hydroxide Alkane extracting, merges dichloromethane layer, and 10mL washing is spin-dried for after saturated sodium-chloride is dry.65 DEG C of 10mL methanol heating are added in crude product Flow back 2h.FLASH column chromatography for separation obtains product 1.01g (yield 55.5%, HPLC purity 87.2%).

MS(ESI⁺,m/e):844.50[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.50 (s, 1H, 9- furans 5-H), 7.24-7.26 (d, J=8Hz, 2H, 3- phenyl ring 2,6-H), 6.84-6.86 (d, J=8Hz, 2H, 3- phenyl ring 3,5-H), 6.85-6.86 (d, J=4Hz, 1H, 9- furans 4-H), 6.46-6.47 (m, J=4Hz, 1H, 9- furans 3-H), 3.78 (s, 3H, 3- phenyl ring 4-OCH₃), 3.60-3.62 (d, J= 8Hz,2H,3-COCH ₂-),2.92(s,3H,6-OCH₃),2.27(s,6H,3’-N(CH₃)₂), 2.26 (s, 3H, 9-N=C-CH₃), 0.80-0.84 (t, J=16Hz, 3H, 13-CH₂CH₃)

¹³CNMR (400M, CDCl3) δ (ppm): 179.4 (1-CO), 173.6 (3-CO), 170.5 (9-N=C-), 144.0 (9-C=N-), 153.4 (9- furans 2-C), 153.2 (9- furans 5-C), 111.6 (9- furans 3-C), 110.7 (9- furans 4- ), C 14.1 (9-C=N-CH₃ ), 158.9 (3- phenyl ring 4-C), 125.7 (3- phenyl ring 1-C), 130.5 (3- phenyl ring 2,6-C), 114.0 (3- phenyl ring, 3,5-C), 55.2 (3-O-CH₃),103.3(1’-CH),40.7(3-CH₂-)

62 3- descladinosylation -3-O- acetyl group -9- of embodiment (1- (furans -2- base) ethylidene hydrazone) clarithromycin (SIPI8519) preparation

MS(ESI⁺,m/e):738.30[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.50 (s, 1H, 9- furans 5-H), 6.85-6.86 (d, J=4Hz, 1H, 9- furans 4-H), 6.46-6.47 (m, J=4Hz, 1H, 9- furans 3-H), 2.93 (s, 3H, 6-OCH₃),2.27(s,6H,3’-N (CH₃)₂), 2.26 (s, 3H, 9-N=C-CH₃),2.12(s,3H,3-CH₃), 0.82-0.86 (t, J=16Hz, 3H, 13- CH₂CH₃)

¹³CNMR (400M, CDCl3) δ (ppm): 180.6 (1-CO), 173.6 (3-CO), 170.5 (9-N=C-), 144.0 (9-C=N-), 153.4 (9- furans 2-C), 153.2 (9- furans 5-C), 111.6 (9- furans 3-C), 110.8 (9- furans 4- ), C 14.1 (9-C=N-CH₃ ),103.3(1’-CH),50.3(6-OCH₃),21.2(3-CH₃)

The preparation of 63 3- descladinosylation -3- hydroxyl -9- of embodiment (1- (thiophene -2- base) ethylidene hydrazone) clarithromycin

3- descladinosylation -3- hydroxyl -9- hydrazone clarithromycin (8.00g, 13.27mmol) is dissolved in 20mL methanol, is added 2- acetyl thiophene (5.02g, 39.8mmol) and glacial acetic acid (2.28mL, 39.8mmol), 65 DEG C are heated to reflux 3h, and reaction solution steams Dry, FLASH column chromatography for separation obtains product 7.41g.(yield 78.6%, HPLC purity 96.6%).MS(ESI⁺,m/e):712.95 [M+H]⁺

Embodiment 64 3- descladinosylation -3-O- (4- fluorobenzene acetyl group) -9- (1- (thiophene -2- base) ethylidene hydrazone) gram Draw the preparation of mycin (SIPI8520)

3- descladinosylation -3- hydroxyl -9- (1- (thiophene -2- base) ethylidene hydrazone) clarithromycin (1.49g, 2.10mmol) It is dissolved in 10mL methylene chloride, is added para-fluorophenylacetic acid (0.97g, 6.30mmol), EDCI (1.21g, 6.30mmol), DMAP (0.03g, 0.1mmol), 25 DEG C of stirring 6h adjust pH to 9-10, liquid separation with 3N sodium hydroxide, and water layer is taken out with 5mL methylene chloride It mentions, merges dichloromethane layer, 10mL washing is spin-dried for after saturated sodium-chloride is dry.Crude product is added 65 DEG C of 10mL methanol and is heated to reflux 2h.FLASH column chromatography for separation obtains product 0.61g (yield 34.4%, HPLC purity 93.5%).

MS(ESI⁺,m/e):848.46[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.37-7.38 (d, J=4Hz1H, 9- thiophene 5-H), 7.33-7.34 (d, J=4Hz, 1H, 9- thiophene 3-H), 7.29-7.32 (q, 2H, J=12Hz, 3- phenyl ring 2,6-H), 6.98-7.02 (t, J=12Hz, 2H, 3- phenyl ring 3,5-H), 7.03-7.05 (t, J=8Hz, 1H, 9- thiophene 4-H), 3.64-3.66 (d, J=8Hz, 2H, 3- COCH ₂-),2.96(s,3H,6-OCH₃), 2.34 (s, 3H, 9-N=C-CH₃),2.27(s,6H,3’-N(CH₃)₂),0.80-0.84 (t, J=16Hz, 3H, 13-CH₂CH₃)

¹³CNMR (400M, CDCl3) δ (ppm): 180.8 (1-CO), 173.4 (3-CO), 171.0 (9-N=C-), 157.2 (9-C=N-), 144.9 (9- thiophene 2-C), 128.5 (9- thiophene 5-C), 127.4 (9- thiophene 3-C), 127.2 (9- thiophene 4- ), C 14.9 (9-C=N-CH₃ ), 163.4 (3- phenyl ring 4-C), 160.9 (3- phenyl ring 1-C), 131.0,129.4 (3- phenyl ring 2,6- ), C 115.5,115.3 (3- phenyl ring, 3,5-C), 103.5 (1 '-CH), 50.4 (6-OCH₃),40.7(3-CH₂-)

Embodiment 65 3- descladinosylation -3-O- (4- chloro acetyl) -9- (1- (thiophene -2- base) ethylidene hydrazone) gram Draw the preparation of mycin (SIPI8521)

3- descladinosylation -3- hydroxyl -9- (1- (thiophene -2- base) ethylidene hydrazone) clarithromycin (1.49g, 2.10mmol) It is dissolved in 10mL methylene chloride, is added 4-Chlorophenylacetic acid (1.07g, 6.30mmol), EDCI (1.21g, 6.30mmol), DMAP (0.03g, 0.1mmol), 25 DEG C of stirring 6h adjust pH to 9-10, liquid separation with 3N sodium hydroxide, and water layer is taken out with 5mL methylene chloride It mentions, merges dichloromethane layer, 10mL washing is spin-dried for after saturated sodium-chloride is dry.Crude product is added 65 DEG C of 10mL methanol and is heated to reflux 2h.FLASH column chromatography for separation obtains product 0.62g (yield 34.3%, HPLC purity 90.2%).

MS(ESI⁺,m/e):864.45[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.37-7.38 (d, J=4Hz1H, 9- thiophene 5-H), 7.33-7.34 (d, J=4Hz, 1H, 9- thiophene 3-H), 7.29 (s, 4H, 3- phenyl ring 2,3,5,6-H), 7.03-7.05 (t, J=8Hz, 1H, 9- thiophene 4-H), 3.65-3.67 (d, J=8Hz, 2H, 3-COCH ₂-),2.95(s,3H,6-OCH₃), 2.34 (s, 3H, 9-N=C-CH₃), 2.27(s,6H,3’-N(CH₃)₂), 0.80-0.84 (t, J=16Hz, 3H, 13-CH₂CH₃)

¹³CNMR (400M, CDCl3) δ (ppm): 180.8 (1-CO), 173.4 (3-CO), 171.7 (9-N=C-), 157.2 (9-C=N-), 144.9 (9- thiophene 2-C), 128.5 (9- thiophene 5-C), 127.4 (9- thiophene 3-C), 127.2 (9- thiophene 4- ), C 14.9 (9-C=N-CH₃ ), 133.3 (3- phenyl ring 4-C), 132.2 (3- phenyl ring 1-C), 130.8 (3- phenyl ring 2,6-C), 128.7 (3- phenyl ring, 3,5-C), 103.5 (1 '-CH), 50.4 (6-OCH₃),40.8(3-CH₂-)

Embodiment 66 3- descladinosylation -3-O- (4- methoxybenzene acetyl group) -9- (1- (thiophene -2- base) ethylidene Hydrazone) clarithromycin (SIPI8522) preparation

3- descladinosylation -3- hydroxyl -9- (1- (thiophene -2- base) ethylidene hydrazone) clarithromycin (1.49g, 2.10mmol) It is dissolved in 10mL methylene chloride, is added homoanisic acid (1.04g, 6.30mmol), EDCI (1.21g, 6.30mmol), DMAP (0.03g, 0.1mmol), 25 DEG C of stirring 6h adjust pH to 9-10, liquid separation, water layer 5mL dichloromethane with 3N sodium hydroxide Alkane extracting, merges dichloromethane layer, and 10mL washing is spin-dried for after saturated sodium-chloride is dry.65 DEG C of 10mL methanol heating are added in crude product Flow back 2h.FLASH column chromatography for separation obtains product 0.85g (yield 47.2%, HPLC purity 92.2%).

MS(ESI⁺,m/e):860.34[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.37-7.38 (d, J=4Hz1H, 9- thiophene 5-H), 7.33-7.34 (d, J=4Hz, 1H, 9- thiophene 3-H), 7.24-7.26 (d, J=8Hz, 2H, 3- phenyl ring 2,6-H), 7.03-7.05 (t, J=8Hz, 1H, 9- thiophene 4-H), 6.84-6.86 (d, J=8Hz, 2H, 3- phenyl ring 3,5-H), 3.78 (s, 3H, 3- phenyl ring 4-OCH₃), 3.61-3.63 (d, J=8Hz, 2H, 3-COCH ₂-),2.95(s,3H,6-OCH₃), 2.34 (s, 3H, 9-N=C-CH₃),2.27 (s,6H,3’-N(CH₃)₂), 0.80-0.84 (t, J=16Hz, 3H, 13-CH₂CH₃)

¹³CNMR (400M, CDCl3) δ (ppm): 180.8 (1-CO), 173.5 (3-CO), 171.4 (9-N=C-), 157.2 (9-C=N-), 144.9 (9- thiophene 2-C), 128.5 (9- thiophene 5-C), 127.4 (9- thiophene 3-C), 127.2 (9- thiophene 4- ), C 14.9 (9-C=N-CH₃ ), 158.9 (3- phenyl ring 4-C), 130.5 (3- phenyl ring 2,6-C), 125.8 (3- phenyl ring 1-C), 114.0 (3- phenyl ring, 3,5-C), 55.3 (3-O-CH₃),103.3(1’-CH),50.4(6-OCH₃),40.7(3-CH₂-)

67 3- descladinosylation -3-O- acetyl group -9- of embodiment (1- (thiophene -2- base) ethylidene hydrazone) clarithromycin (SIPI8523) preparation

3- descladinosylation -3- hydroxyl -9- (1- (thiophene -2- base) ethylidene hydrazone) clarithromycin (1.49g, 2.10mmol) It is dissolved in 10mL methylene chloride, is added acetic anhydride (0.43g, 4.20mmol), EDCI (1.21g, 6.30mmol), DMAP (0.03g, 0.1mmol), 25 DEG C of stirring 6h adjust pH to 9-10, liquid separation with 3N sodium hydroxide, and water layer is taken out with 5mL methylene chloride It mentions, merges dichloromethane layer, 10mL washing is spin-dried for after saturated sodium-chloride is dry.Crude product is added 65 DEG C of 10mL methanol and is heated to reflux 2h.FLASH column chromatography for separation obtains product 0.77g (yield 48.8%, HPLC purity 93.7%).

MS(ESI⁺,m/e):754.27[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.37-7.38 (d, J=4Hz1H, 9- thiophene 5-H), 7.33-7.34 (d, J=4Hz, 1H, 9- thiophene 3-H), 7.03-7.05 (t, J=8Hz, 1H, 9- thiophene 4-H), 2.96 (s, 3H, 6-OCH₃),2.34 (s, 3H, 9-N=C-CH₃),2.27(s,6H,3’-N(CH₃)₂),2.12(s,3H,3-CH₃), 0.80-0.84 (t, J=16Hz, 3H,13-CH₂CH₃)

¹³CNMR (400M, CDCl3) δ (ppm): 180.8 (1-CO), 173.6 (3-CO), 170.4 (9-N=C-), 157.1 (9-C=N-), 144.9 (9- thiophene 2-C), 128.5 (9- thiophene 5-C), 127.4 (9- thiophene 3-C), 127.2 (9- thiophene 4- ), C 14.9 (9-C=N-CH₃ ),103.3(1’-CH),50.4(6-OCH₃),21.2(3-CH₃)

The preparation of embodiment 68 3- descladinosylation -3- hydroxyl -9- (biphenyl ethylidene hydrazone) clarithromycin

3- descladinosylation -3- hydroxyl -9- hydrazone clarithromycin (8.00g, 13.27mmol) is dissolved in 30mL methanol, is added 4-acetylbiphenyl (7.80g, 39.8mmol) and glacial acetic acid (2.38mL, 39.8mmol), 65 DEG C are heated to reflux 3h., reaction solution is evaporated, FLASH column chromatography for separation obtains product 5g.(yield 48.2%, HPLC purity 95.4%).MS(ESI⁺,m/e):783.02[M+H]⁺

Embodiment 69 3- descladinosylation -3-O- (4- fluorobenzene acetyl group) -9- (biphenyl ethylidene hydrazone) clarithromycin (SIPI8524) preparation

3- descladinosylation -3- hydroxyl -9- (biphenyl ethylidene hydrazone) clarithromycin (2.00g, 2.56mmol) is dissolved in 10mL In methylene chloride, it is added para-fluorophenylacetic acid (1.58g, 10.24mmol), EDCI (1.97g, 10.24mmol), DMAP (0.03g, 0.1mmol), 25 DEG C of stirring 6h adjust pH to 9-10, liquid separation with 3N sodium hydroxide, and water layer is extracted with 5mL methylene chloride, is merged Dichloromethane layer, 10mL washing are spin-dried for after saturated sodium-chloride is dry.Crude product is added 65 DEG C of 10mL methanol and is heated to reflux 2h.FLASH Column chromatography for separation obtains product 0.42g (yield 17.9%, HPLC purity 97.4%).

MS(ESI⁺,m/e):918.32[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.95-7.97 (d, J=8Hz, 2H, 9- biphenyl 3,5-H), 7.64-7.65 (d, J=4Hz, 2H, 9- biphenyl 2,6-H), 7.62-7.63 (d, J=4Hz, 2H, 9- biphenyl, 2 ', 6 '-H), 7.43-7.47 (t, J =12Hz, 2H, 3 ', 5 '-H of 9- biphenyl), 7.33-7.37 (4 '-H of t, J=12Hz, 1H, 9- biphenyl), 7.29-7.32 (q, J= 12Hz, 2H, 3- phenyl ring 2,6-H), 6.98-7.02 (t, J=12Hz, 2H, 3- phenyl ring 3,5-H), 3.65-3.67 (d, J=8Hz, 2H,3-COCH ₂-),2.95(s,3H,6-OCH₃), 2.36 (s, 3H, 9-N=C-CH₃),2.28(s,6H,3’-N(CH₃)₂), 0.80-0.84 (t, J=16Hz, 3H, 13-CH₂CH₃)

¹³CNMR (400M, CDCl3) δ (ppm): 179.2 (1-CO), 173.4 (3-CO), 171.0 (9-N=C-), 160.3 (9-C=N-), 142.4 (9- biphenyl 1-C), 140.5 (1 '-C of 9- biphenyl), 137.6 (9- biphenyl 4-C), 128.8,127.5, 127.0 (2,3,5,6,2 ', 3 ', 5 ', 6 '-C of 9- biphenyl), 126.9 (4 '-C of 9- biphenyl), 14.8 (9-C=N-CH₃ ),163.4 (3- phenyl ring 4-C), 160.9 (3- phenyl ring 1-C), 131.0,129.4 (3- phenyl ring 2,6-C), 115.5,115.3 (3- phenyl ring, 3,5- C),103.4(1’-CH),50.5(6-OCH₃),40.7(3-CH₂-)

Embodiment 70 3- descladinosylation -3-O- (4- chloro acetyl) -9- (biphenyl ethylidene hydrazone) clarithromycin (SIPI8525) preparation

3- descladinosylation -3- hydroxyl -9- (biphenyl ethylidene hydrazone) clarithromycin (1.50g, 1.92mmol) is dissolved in 10ml In methylene chloride, it is added 4-Chlorophenylacetic acid (1.31g, 7.68mmol), EDCI (1.47g, 7.68mmol), DMAP (0.03g, 0.1mmol), 6h being stirred at room temperature for 25 DEG C, adjusts pH to 9-10, liquid separation with 3N sodium hydroxide, water layer is extracted with 5ml methylene chloride, Merge dichloromethane layer, 10ml washing is spin-dried for after saturated sodium-chloride is dry.Crude product is added 65 DEG C of 10ml methanol and is heated to reflux 2h. FLASH column chromatography for separation obtains product 0.85g (yield 47.4%, HPLC purity 98.4%).

MS(ESI⁺,m/e):934.45[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.95-7.97 (d, J=8Hz, 2H, 9- biphenyl 3,5-H), 7.64-7.65 (d, J=4Hz, 2H, 9- biphenyl 2,6-H), 7.62-7.63 (d, J=4Hz, 2H, 9- biphenyl, 2 ', 6 '-H), 7.43-7.47 (t, J =12Hz, 2H, 3 ', 5 '-H of 9- biphenyl), 7.33-7.37 (4 '-H of t, J=12Hz, 1H, 9- biphenyl), 7.29 (s, 4H, 3- phenyl ring 2,3,5,6-H),2.95(s,3H,6-OCH₃), 3.64-3.66 (d, J=8Hz, 2H, 3-COCH₂), 2.36 (s, 3H, 9-N=C- CH₃),2.28(s,6H,3’-N(CH₃)₂), 0.80-0.84 (t, J=16Hz, 3H, 13-CH₂CH₃)

¹³CNMR (400M, CDCl3) δ (ppm): 179.1 (1-CO), 173.4 (3-CO), 171.7 (9-N=C-), 160.2 (9-C=N-), 142.3 (9- biphenyl 1-C), 140.4 (1 '-C of 9- biphenyl), 137.5 (9- biphenyl 4-C), 128.8,127.5, 127.0 (2,3,5,6,2 ', 3 ', 5 ', 6 '-C of 9- biphenyl), 126.9 (4 '-C of 9- biphenyl), 14.7 (9-C=N-CH₃ ),133.3 (3- phenyl ring 4-C), 132.2 (3- phenyl ring 1-C), 130.8 (3- phenyl ring 2,6-C), 128.7 (3- phenyl ring, 3,5-C), 103.2 (1 '- CH),50.4(6-OCH₃),40.7(3-CH₂-)

Embodiment 71 3- descladinosylation -3-O- (4- methoxybenzene acetyl group) -9- (biphenyl ethylidene hydrazone) clarithromycin (SIPI8526) preparation

3- descladinosylation -3- hydroxyl -9- (biphenyl ethylidene hydrazone) clarithromycin (1.50g, 1.92mmol) is dissolved in 10mL In methylene chloride, it is added homoanisic acid (0.98g, 5.90mmol), EDCI (1.11g, 5.76mmol), DMAP (0.03g, 0.1mmol), 25 DEG C of stirring 6h adjust pH to 9-10, liquid separation with 3N sodium hydroxide, and water layer is taken out with 5mL methylene chloride It mentions, merges dichloromethane layer, 10mL washing is spin-dried for after saturated sodium-chloride is dry.Crude product is added 65 DEG C of 10mL methanol and is heated to reflux 2h.FLASH column chromatography for separation obtains product 0.42g (yield 23.5%, HPLC purity 100%).

MS(ESI⁺,m/e):930.46[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.95-7.97 (d, J=8Hz, 2H, 9- biphenyl 3,5-H), 7.64-7.65 (d, J=4Hz, 2H, 9- biphenyl 2,6-H), 7.62-7.63 (d, J=4Hz, 2H, 9- biphenyl, 2 ', 6 '-H), 7.43-7.47 (t, J =12Hz, 2H, 3 ', 5 '-H of 9- biphenyl), 7.33-7.37 (4 '-H of t, J=12Hz, 1H, 9- biphenyl), 7.24-7.26 (d, J= 8Hz, 2H, 3- phenyl ring 2,6-H), 6.84-6.86 (d, J=8Hz, 2H, 3- phenyl ring 3,5-H), 3.78 (s, 3H, 3- phenyl ring 4- OCH₃), 3.61-3.63 (d, J=8Hz, 2H, 3-COCH ₂-),2.95(s,3H,6-OCH₃), 2.36 (s, 3H, 9-N=C-CH₃), 2.28(s,6H,3’-N(CH₃)₂), 0.80-0.84 (t, J=16Hz, 3H, 13-CH₂CH₃)

¹³CNMR (400M, CDCl3) δ (ppm): 179.3 (1-CO), 173.6 (3-CO), 171.5 (9-N=C-), 160.3 (9-C=N-), 142.3 (9- biphenyl 1-C), 140.6 (1 '-C of 9- biphenyl), 137.7 (9- biphenyl 4-C), 128.8,127.6, 127.0 (2,3,5,6,2 ', 3 ', 5 ', 6 '-C of 9- biphenyl), 127.0 (4 '-C of 9- biphenyl), 14.8 (9-C=N-CH ₃),160.0 (3- phenyl ring 4-C), 130.5 (3- phenyl ring 2,6-C), 125.8 (3- phenyl ring 1-C), 114.1 (3- phenyl ring, 3,5-C), 55.5 (3-O- CH₃),103.3(1’-CH),50.5(6-OCH₃),40.7(3-CH₂-)

Embodiment 72 3- descladinosylation -3-O- acetyl group -9- (biphenyl ethylidene hydrazone) clarithromycin (SIPI8527) Preparation

3- descladinosylation -3- hydroxyl -9- (biphenyl ethylidene hydrazone) clarithromycin (1.50g, 1.92mmol) is dissolved in 10mL In methylene chloride, it is added acetic anhydride (0.39g, 3.84mmol), EDCI (1.11g, 5.76mmol), DMAP (0.03g, 0.1mmol), 25 DEG C of stirring 6h adjust pH to 9-10, liquid separation with 3N sodium hydroxide, and water layer is extracted with 5mL methylene chloride, is merged Dichloromethane layer, 10mL washing are spin-dried for after saturated sodium-chloride is dry.Crude product is added 65 DEG C of 10mL methanol and is heated to reflux 2h.FLASH Column chromatography for separation obtains product 0.94g (yield 59.7%, HPLC purity 96.3%).

MS(ESI⁺,m/e):824.40[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.95-7.97 (d, J=8Hz, 2H, 9- biphenyl 3,5-H), 7.64-7.65 (d, J=4Hz, 2H, 9- biphenyl 2,6-H), 7.62-7.63 (d, J=4Hz, 2H, 9- biphenyl, 2 ', 6 '-H), 7.43-7.47 (t, J =12Hz, 2H, 3 ', 5 '-H of 9- biphenyl), 7.33-7.37 (4 '-H of t, J=12Hz, 1H, 9- biphenyl), 2.95 (s, 3H, 6- OCH₃), 2.36 (s, 3H, 9-N=C-CH₃),2.28(s,6H,3’-N(CH₃)₂),2.12(s,3H,3-CH₃),0.80-0.84(t, J=16Hz, 3H, 13-CH₂CH₃)

¹³CNMR (400M, CDCl3) δ (ppm): 179.2 (1-CO), 173.6 (3-CO), 170.5 (9-N=C-), 160.2 (9-C=N-), 142.3 (9- biphenyl 1-C), 140.5 (1 '-C of 9- biphenyl), 137.6 (9- biphenyl 4-C), 128.8,127.5, 127.0 (2,3,5,6,2 ', 3 ', 5 ', 6 '-C of 9- biphenyl), 126.9 (4 '-C of 9- biphenyl), 14.8 (9-C=N-CH₃ ),103.3 (1’-CH),50.5(6-OCH₃),21.2(3-CH₃)

Embodiment 73 3- descladinosylation -3-O- (4- fluorobenzene acetyl group) Asia -9- second propyl hydrazone clarithromycin (SIPI8528) preparation

3- descladinosylation -3- hydroxyl -9- isopropylidene hydrazone clarithromycin (2.00g, 3.10mmol) is dissolved in 5mL dichloromethane In alkane, it is added para-fluorophenylacetic acid (1.43g, 9.3mmol), EDCI (1.79g, 9.3mmol), DMAP (0.03g, 0.1mmol), 25 DEG C stirring 6h, with 3N sodium hydroxide adjust pH to 9-10, liquid separation, water layer with 5mL methylene chloride extract, merge dichloromethane layer, 10mL washing is spin-dried for after saturated sodium-chloride is dry.Crude product is added 65 DEG C of 10mL methanol and is heated to reflux 2h.FLASH column chromatography for separation It obtains product 1.3g (yield 53.7%, HPLC purity 97.8%).

MS(ESI⁺,m/e):780.31[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.29-7.32 (q, J=12Hz, 2H, 3- phenyl ring 2,6-H), 6.98- 7.02 (t, J=12Hz, 2H, 3- phenyl ring 3,5-H), 3.65-3.67 (d, J=8Hz, 2H, 3-COCH ₂-),2.95(s,3H,6- OCH₃), 2.36 (s, 3H, 9-N=C-CH₃),2.28(s,6H,3’-N(CH₃)₂),2.12(s,3H,3-CH₃),2.03(s,3H,9- N=C (CH₃)₂), 1.93 (s, 3H, 9-N=C (CH₃)₂), 0.80-0.84 (t, J=16Hz, 3H, 13-CH₂CH₃)

¹³CNMR (400M, CDCl3) δ (ppm): 179.0 (1-CO), 173.4 (3-CO), 171.0 (9-N=C-), 163.2 (9-C=N-), 25.4,18.4 (9-N=C- (CH₃ )₂), 163.2 (3- phenyl ring 4-C), 160.9 (3- phenyl ring 1-C), 131.0, 129.4 (3- phenyl ring 2,6-C), 115.5,115.3 (3- phenyl ring, 3,5-C), 103.6 (1 '-CH), 50.3 (6-OCH₃),40.7 (3-CH₂-)

Embodiment 74 3- descladinosylation -3-O- (4- chloro acetyl) Asia -9- second propyl hydrazone clarithromycin (SIPI8529) preparation

3- descladinosylation -3- hydroxyl -9- isopropylidene hydrazone clarithromycin (2.00g, 3.10mmol) is dissolved in 5mL dichloromethane In alkane, it is added 4-Chlorophenylacetic acid (1.59g, 9.3mmol), EDCI (1.79g, 9.3mmol), DMAP (0.03g, 0.1mmol), 25 DEG C stirring 6h, with 3N sodium hydroxide adjust pH to 9-10, liquid separation, water layer with 5mL methylene chloride extract, merge dichloromethane layer, 10mL washing is spin-dried for after saturated sodium-chloride is dry.Crude product is added 65 DEG C of 10mL methanol and is heated to reflux 2h.FLASH column chromatography for separation It obtains product 1.16g (yield 46.9%, HPLC purity 92.1%).

MS(ESI⁺,m/e):796.27[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.26 (s, 4H, 3- phenyl ring 2,3,5,6-H), 2.95 (s, 3H, 6- OCH₃), 3.65-3.67 (d, J=8Hz, 2H, 3-COCH ₂), 2.36 (s, 3H, 9-N=C-CH₃),2.28(s,6H,3’-N (CH₃)₂), 2.03 (s, 3H, 9-N=C (CH₃)₂), 1.93 (s, 3H, 9-N=C (CH₃)₂), 0.80-0.84 (t, J=16Hz, 3H, 13-CH₂CH₃)

¹³CNMR (400M, CDCl3) δ (ppm): 179.0 (1-CO), 173.4 (3-CO), 171.0 (9-N=C-), 163.2 (9-C=N-), 25.4,18.3 (9-N=C- (CH₃ )₂), 28.6 (9-N=C-CH₃ ), 133.3 (3- phenyl ring 4-C), 132.2 (3- Phenyl ring 1-C), 130.8 (3- phenyl ring 2,6-C), 128.7 (3- phenyl ring, 3,5-C), 103.5 (1 '-CH), 50.2 (6-OCH₃), 40.7(3-CH₂-)

Embodiment 75 3- descladinosylation -3-O- (4- methoxybenzene acetyl group) Asia -9- second propyl hydrazone clarithromycin (SIPI8530) preparation

3- descladinosylation -3- hydroxyl -9- isopropylidene hydrazone clarithromycin (2.00g, 3.10mmol) is dissolved in 5mL dichloromethane In alkane, it is added homoanisic acid (1.03g, 6.2mmol), EDCI (1.79g, 9.3mmol), DMAP (0.03g, 0.1mmol), 25 DEG C of stirring 6h adjust pH to 9-10, liquid separation with 3N sodium hydroxide, and water layer is extracted with 5mL methylene chloride, is merged Dichloromethane layer, 10mL washing are spin-dried for after saturated sodium-chloride is dry.Crude product is added 65 DEG C of 10mL methanol and is heated to reflux 2h.FLASH Column chromatography for separation obtains product 0.84g (yield 34.1%, HPLC purity 97.9%).

MS(ESI⁺,m/e):792.36[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.24-7.26 (d, J=8Hz, 2H, 3- phenyl ring 2,6-H), 6.84-6.86 (d, J=8Hz, 2H, 3- phenyl ring 3,5-H), 3.78 (s, 3H, 3- phenyl ring 4-OCH₃), 3.60-3.62 (d, J=8Hz, 2H, 3- COCH ₂-),2.95(s,3H,6-OCH₃), 2.36 (s, 3H, 9-N=C-CH₃),2.28(s,6H,3’-N(CH₃)₂),2.03(s, 3H, 9-N=C (CH₃)₂), 1.93 (s, 3H, 9-N=C (CH₃)₂), 0.80-0.84 (t, J=16Hz, 3H, 13-CH₂CH₃)

¹³CNMR (400M, CDCl3) δ (ppm): 179.0 (1-CO), 173.5 (3-CO), 171.5 (9-N=C-), 163.1 (9-C=N-), 25.4,18.3 (9-N=C- (CH₃ )₂), 158.9 (3- phenyl ring 4-C), 130.4 (3- phenyl ring 2,6-C), 125.7 (3- phenyl ring 1-C), 114.0 (3- phenyl ring, 3,5-C), 55.2 (3-O-CH₃),103.3(1’-CH),50.3(6-OCH₃),40.6 (3-CH₂-)

76 3- descladinosylation -3-O- acetyl group -9- Asia second propyl hydrazone clarithromycin (SIPI8531) of embodiment

3- descladinosylation -3- hydroxyl -9- isopropylidene hydrazone clarithromycin (2.00g, 3.10mmol) is dissolved in 5mL dichloromethane In alkane, it is added acetic anhydride (0.63g, 6.20mmol), EDCI (1.79g, 9.3mmol), DMAP (0.03g, 0.1mmol), 25 DEG C 6h is stirred, adjusts pH to 9-10, liquid separation with 3N sodium hydroxide, water layer is extracted with 5mL methylene chloride, merge dichloromethane layer, 10mL washing is spin-dried for after saturated sodium-chloride is dry.Crude product is added 65 DEG C of 10mL methanol and is heated to reflux 2h.FLASH column chromatography for separation It obtains product 1.11g (yield 52.1%, HPLC purity 93.8%).

MS(ESI⁺,m/e):686.21[M+H]⁺

¹HNMR(400MHz,CDCl₃)δ(ppm):2.95(s,3H,6-OCH₃), 2.36 (s, 3H, 9-N=C-CH₃),2.28 (s,6H,3’-N(CH₃)₂),2.12(s,3H,3-CH₃), 2.00 (s, 3H, 9-N=C (CH₃)₂), 1.91 (s, 3H, 9-N=C (CH₃)₂), 0.80-0.84 (t, J=16Hz, 3H, 13-CH₂CH₃)

¹³CNMR (400M, CDCl3) δ (ppm): 179.0 (1-CO), 173.5 (3-CO), 171.5 (9-N=C-), 163.1 (9-C=N-), 25.4,18.3 (9-N=C- (CH₃ )₂),103.3(1’-CH),50.3(6-OCH₃),21.2(3-CH₃)

The preparation of 77 9- hydrazone erythromycin thiocyanate A of embodiment

Erythromycin thiocyanate A (200g, 0.25mmol) is dissolved in 200mL methanol, and the hydration that mass percent is 85% is added Hydrazine (21.5mL, 0.36mmol), 65 DEG C are heated to reflux 18h.6 DEG C are cooled to, solid, filtering is precipitated, filter cake is washed with ice methanol Dry crude product 147g (yield 72.7%) afterwards.

78 3- descladinosylation -3- hydroxyl -9- hydrazone Erythromycin A of embodiment

9- hydrazone erythromycin thiocyanate A (10g, 12.4mmol) is dissolved in the hydrochloric acid (50mL) that molar concentration is 1N, and 25 DEG C are stirred Mix 4h.Methylene chloride 50mL is added, adjusts pH to 10, liquid separation with 3N sodium hydroxide, water layer is extracted with methylene chloride 20mL, is merged Dichloromethane layer, washing are evaporated after saturated sodium-chloride is dry, obtain crude product 8g.

The system of embodiment 79 3- descladinosylation -3- hydroxyl -9- (4- fluorobenzene ethylidene) hydrazone Erythromycin A (SIPI8411) It is standby

(8g, 13.5mmol are dissolved in 50mL methanol to 3- descladinosylation -3- hydroxyl -9- hydrazone Erythromycin A, are added to fluorophenethyl Ketone (2.8g, 20.3mmol), glacial acetic acid (1.2mL, 20.3mmol), 65 DEG C are heated to reflux 4h.Methylene chloride 80mL, water is added 60mL adjusts pH to 10, liquid separation with 3N sodium hydroxide, and water layer is extracted with 20mL methylene chloride, merges dichloromethane layer, washes, Crude product 8.8g is evaporated to obtain after saturated sodium-chloride is dry.0.5g FLASH column chromatography for separation is taken to obtain product 0.26g (yield 47.7%). MS(ESI⁺,m/e):710.21[M+H]⁺

Embodiment 80 3- descladinosylation -3-O- (4- fluorobenzene acetyl group) -9- (4- fluorobenzene ethylidene) hydrazone Erythromycin A (SIPI8412) preparation

3- descladinosylation -3- hydroxyl -9- (4- fluorobenzene ethylidene) hydrazone erythromycin (1g, 1.4mmol) is dissolved in 5mL dichloromethane Alkane is added 4- fluorophenylacetic acid (1.1g, 7mmol), EDCI (2.2g, 8.4mmol), 25 DEG C of stirring 16h.Methylene chloride 5mL is added, Water 10mL adjusts pH to 10 with 3N sodium hydroxide, and washing is evaporated after saturated sodium-chloride is dry.The solid being evaporated is dissolved in 10mL first Alcohol, 65 DEG C are heated to reflux 4h, are evaporated, and FLASH column chromatography for separation obtains product 0.17g (14.3%, HPLC purity 94.0%).MS (ESI⁺,m/e):846.45[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.82-7.8 (m, 2H, 9- phenyl ring 2,6-H), 7.78-7.26 (m, 2H, 3- Phenyl ring 3,5-H), 7.11-6.99 (m, 4H, 3- phenyl ring 2,6-H, 9- phenyl ring 3,5-H)

¹³CNMR(400M,CDCl₃) δ (ppm): 178.6 (1-CO), 173.0 (3-CO), 170.6 (9-C=N-), 165.3 (9- phenyl ring 4-C), 160.1 (3- phenyl ring 4-C), 133.7-115.3 (3,9- phenyl ring C)

Embodiment 81 3- descladinosylation -3-O- (3,4,5- trifluoro phenylacetyl group) -9- (4- fluorobenzene ethylidene) hydrazone is red mould The preparation of plain A (SIPI8413)

Preparation method same SIPI8412,3- descladinosylation -3- hydroxyl -9- (4- fluorobenzene ethylidene) hydrazone erythromycin (1g, 1.4mmol) feed intake to obtain product 0.22g (yield 18.1%, HPLC purity 90.1%).

MS(ESI⁺,m/e):882.55[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.82-7.78 (m, 2H, 9- phenyl ring 2,6-H), 7.21-6.90 (m, 4H, 9- phenyl ring 3,5-H, 3- phenyl ring 2,6-H), 3.69 (d, J=4.8Hz, 2H, 3-COCH₂), 2.25 (s, 3H, 9-N=C-CH₃)

¹³CNMR(400M,CDCl₃) δ (ppm): 173.0 (3-CO), 169.3 (9-C=N-), 165.3 (9- phenyl ring 4-C), 160.2 (9-N=C-), 133.7-105.2 (3,9- phenyl ring C), 33.6 (3-CH₂),30.2(9-CH₃)

Embodiment 82 3- descladinosylation -3-O- (3,5- difluoro phenylacetyl group) -9- (4- fluorobenzene ethylidene) hydrazone erythromycin The preparation of A (SIPI8414)

Preparation method same SIPI8412,3- descladinosylation -3- hydroxyl -9- (4- fluorobenzene ethylidene) hydrazone erythromycin (1g, 1.4mmol) feed intake to obtain product 0.26g (yield 20.9%, HPLC purity 94.5%).

MS(ESI⁺,m/e):864.45[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.82-7.78 (m, 2H, 9- phenyl ring 2,6-H), 7.11-7.07 (t, 2H, 9- phenyl ring 3,5-H), 6.91-6.69 (m, 3H, 3- phenyl ring H), 3.67 (d, J=4.8Hz, 2H, 3-COCH₂-),2.25(s,3H, 9-N=C-CH₃)

¹³CNMR(400M,CDCl₃) δ (ppm): 173.0 (3-CO), 169.3 (9-C=N-), 165.3-161.9 (9- phenyl ring 4-C, 3- phenyl ring 3,5-C), 160.2 (9-N=C-), 137.3-103.8 (3,9- phenyl ring C), 41.0 (3-CH₂),30.2(9-CH₃)

Embodiment 83 2 '-O- acetyl group -3- descladinosylation -3- hydroxyl -9- (4- methoxybenzene ethylidene hydrazone) carat is mould The preparation of element

3- descladinosylation -3- hydroxyl -9- (4- methoxybenzene ethylidene hydrazone) clarithromycin (SIPI8905) (14.4g, It 20mmol) is dissolved in 30mL methylene chloride, is added acetic anhydride (3.4mL, 60mmol), 25 DEG C of stirring 4h.Water 30mL is added, uses 3N Sodium hydroxide adjusts pH to 10, liquid separation, and water layer is extracted with methylene chloride 15mL, merges dichloromethane layer, washing, saturated sodium-chloride Crude product 14.6g (HPLC purity 95.4%) is evaporated to obtain after drying.

Embodiment 84 3- descladinosylation -3-O- (3,5- difluoro phenylacetyl group) -9- (4- methoxybenzene ethylidene hydrazone) gram Draw the preparation of mycin (SIPI8551)

2 '-O- acetyl group -3- descladinosylation -3- hydroxyl -9- (4- methoxybenzene ethylidene hydrazone) clarithromycin (1.55g, It 2mmol) is dissolved in methylene chloride 10mL, is added 3,5- difluorophenyl acetic acid (0.7g, 4mmol), EDCI (0.79g, 4mmol), ice Acetic acid (0.23mL, 4mmol), 25 DEG C of stirring 16h.Be added methylene chloride 10mL, water 20mL, with 3N sodium hydroxide adjust pH to 10, liquid separation, water layer is extracted with 10mL methylene chloride, merges dichloromethane layer, and washing is evaporated after saturated sodium-chloride is dry, is added Methanol 10mL, 65 DEG C be heated to reflux 4h after be evaporated, FLASH column chromatography for separation obtains product 0.5g (yield 28.6%, HPLC purity 95.5%).

MS(ESI⁺,m/e):890.30[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.86-7.83 (2H, 9- phenyl ring 2,6-H), 6.95-6.89 (4H, 9- benzene Ring 3,5-H, 3- phenyl ring 2,6-H), 6.72 (1H, 3- phenyl ring 4-H)

¹³CNMR(400M,CDCl₃) δ (ppm): 178.9 (1-CO), 173.3 (3-CO), 170.0 (9-C=N-), 161.7 (9-N=C-), 164.3-164.2 (3- phenyl ring 3,5-C), 137.3 (9- phenyl ring 1C), 131.4 (3- phenyl ring 1C), 128.5- 102.8 (3,9- phenyl ring C), 55.3 (9-OCH₃),50.4(6-OCH₃),40.3(3-CH₂)

Embodiment 85 3- descladinosylation -3-O- (3,5- difluoro phenylacetyl group) -9- (4- methoxybenzene ethylidene hydrazone) gram It draws mycin (SIPI8552)

The same SIPI8551 of preparation method, 2 '-O- acetyl group -3- descladinosylation -3- hydroxyl -9- (4- methoxybenzene Asia second Base hydrazone) clarithromycin (1.55g, 2mmol) feeds intake to obtain product 0.55g (yield 28.4%, HPLC purity 94.0%)

MS(ESI⁺,m/e):922.32[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.86-7.84 (2H, 9- phenyl ring 2,6-H), 7.60-7.58 (2H, 3- benzene Ring 3,5-H), 7.49-7.47 (2H, 9- phenyl ring 3,5-H), 6.93-6.90 (2H, 3- phenyl ring 2,6-H)

¹³CNMR(400M,CDCl₃) δ (ppm): 178.9 (1-CO), 173.3 (3-CO), 169.7 (9-C=N-), 161.0 (9-N=C-), 160.2 (9- phenyl ring 4-C), 137.8 (3- phenyl ring 1-C), 131.4-113.7 (3,9- phenyl ring C), 55.3 (9- OCH₃),50.4(6-OCH₃),40.3(3-CH₂)

Embodiment 86 3- descladinosylation -3-O- (3,5- difluoro phenylacetyl group) -9- (4- methoxybenzene ethylidene hydrazone) gram It draws mycin (SIPI8553)

The same SIPI8551 of preparation method, 2 '-O- acetyl group -3- descladinosylation -3- hydroxyl -9- (4- methoxybenzene Asia second Base hydrazone) clarithromycin (1.55g, 2mmol) feeds intake to obtain product 0.58g (yield 30.4%, HPLC purity 96.8%) MS (ESI⁺, m/e):908.38[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.80 (d, J=8.0Hz, 2H, 9- phenyl ring 2,6-H), 7.25-7.16 (m, 1H, 3- phenyl ring 3-H), 6.96-6.90 (m, 3H, 9- phenyl ring 3,5-H3- phenyl ring 6-H)

¹³CNMR(400M,CDCl₃) δ (ppm): 178.9 (1-CO), 173.3 (3-CO), 169.7 (9-C=N-), 161.0 (9-N=C-), 160.2 (9- phenyl ring 4-C), 105.2-131.4 (3,9- phenyl ring C), 55.3 (9-OCH₃),50.4(6-OCH₃), 40.3(3-CH₂)

Embodiment 87 3- descladinosylation -3- hydroxyl -9- (4- methoxybenzylidene hydrazone) clarithromycin

3- descladinosylation -3- hydroxyl -9- hydrazone clarithromycin (SIPI8903) (12g, 20mmol) is dissolved in 36mL methanol, adds Enter 4-methoxybenzaldehyde (3.6mL, 30mmol), glacial acetic acid (1.7mL, 30mmol), 65 DEG C are heated to reflux 4h.Dichloromethane is added Alkane 40mL, water 40mL adjust pH to 10, liquid separation with 3N sodium hydroxide, and water layer is extracted with 10mL methylene chloride, merges methylene chloride Layer, washing obtain crude product 15.2g after being evaporated after saturated sodium-chloride is dry, 1g crude product column chromatography for separation are taken to obtain product 0.21g, yield 21.9%.MS(ESI⁺,m/e):722.92[M+H]⁺

Embodiment 88 2 '-O- acetyl group -3- descladinosylation -3- hydroxyl -9- (4- methoxybenzylidene hydrazone) carat is mould Element

3- descladinosylation -3- hydroxyl -9- (4- methoxybenzylidene hydrazone) clarithromycin 14.2g is dissolved in 20mL dichloromethane Alkane is added acetic anhydride (5.6mL, 60mmol), 25 DEG C of stirring 4h.Add water 40mL, with 3N sodium hydroxide adjust pH to 10, liquid separation, Water layer is extracted with 10mL methylene chloride, merges dichloromethane layer, and washing is evaporated to obtain crude product 15.3g after saturated sodium-chloride is dry, slightly Product yield 102.0%.

Embodiment 89 3- descladinosylation -3-O- (4- fluorobenzene acetyl group) -9- (4- methoxybenzylidene hydrazone) carat is mould The preparation of plain (SIPI8554)

2 '-O- acetyl group -3- descladinosylation -3- hydroxyl -9- (4- methoxybenzylidene hydrazone) clarithromycin (1.52g, It 2mmol) is dissolved in methylene chloride 10mL, is added 4- fluorophenylacetic acid (0.56g, 4mmol), EDCI (0.79g, 4mmol), glacial acetic acid (0.23mL, 4mmol), 25 DEG C of stirring 16h.Methylene chloride 10mL, water 20mL is added, adjusts pH to 10 with 3N sodium hydroxide, point Liquid, water layer are extracted with 10mL methylene chloride, merge dichloromethane layer, and washing is evaporated after saturated sodium-chloride is dry, methanol is added 10mL, 65 DEG C be heated to reflux 4h after be evaporated, FLASH column chromatography for separation obtains product 0.22g (yield 12.9%, HPLC purity 92.8%).MS(ESI⁺,m/e):858.42[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 8.25 (s, 1H, 9-N=CH-), 7.70 (d, J=8.8Hz, 2H, 9- benzene Ring 2,6-H), 7.31-7.27 (m, 2H, 3- phenyl ring 2,6-H), 7.02-6.91 (m, 4H, 3,9- phenyl ring 3,5-H), 3.84 (s, 3H, 9- phenyl ring 4-OCH₃), 3.64 (d, J=9.2Hz, 2H, 3-COCH₂-),2.87(s,3H,6-OCH₃)

¹³CNMR(400M,CDCl₃) δ (ppm): 173.4 (3-CO), 171.0 (9-C=N-), 163.4-160.9 (9- phenyl ring 4-C, 3- phenyl ring 4-C), 158.3 (9-N=C-), 131.1-114.3 (3,9- phenyl ring C), 55.3 (9-OCH₃),50.5(6- OCH₃),40.7(3-CH₂)

Embodiment 90 3- descladinosylation -3-O- (4- chloro acetyl) -9- (4- methoxybenzylidene hydrazone) carat is mould The preparation of plain (SIPI8555)

The same SIPI8554 of preparation method, 2 '-O- acetyl group -3- descladinosylation -3- hydroxyl -9- (4- methoxybenzene methylenes Base hydrazone) clarithromycin (1.52g, 2mmol) feeds intake to obtain product 0.45g (yield 25.8%, HPLC purity 87.3%).MS(ESI⁺, m/e):874.38[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 8.25 (s, 1H, 9-N=CH-), 7.71-7,69 (2H, 9- phenyl ring 2,6- ), H 7.34-7.25 (4H, 3- phenyl ring 2,3,5,6-H), 6.96-6.91 (9- phenyl ring 3,5-H)

¹³CNMR(400M,CDCl₃) δ (ppm): 182.8 (1-CO), 173.3 (3-CO), 170.7 (9-C=N-), 161.8 (9-N=C-), 158.3 (9- phenyl ring 4-C), 133.3-127.5 (3,9- phenyl ring C), 114.6-114.3 (9- phenyl ring 3,5-C), 55.3(9-OCH₃),50.4(6-OCH₃),40.8(3-CH₂)

Embodiment 91 3- descladinosylation -3-O- (4- trifluoromethyl phenylacetyl group) -9- (4- methoxybenzylidene hydrazone) The preparation of clarithromycin (SIPI8556)

The same SIPI8554 of preparation method, 2 '-O- acetyl group -3- descladinosylation -3- hydroxyl -9- (4- methoxybenzene methylenes Base hydrazone) clarithromycin (1.52g, 2mmol) feeds intake to obtain product 0.61g (yield 33.7%, HPLC purity 90.6%).MS(ESI⁺, m/e):908.41[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 8.31 (s, 1H, 9-N=CH-), 7.71-7,69 (2H, 9- phenyl ring 2,6- ), H 7.66-7.64 (2H, 3- phenyl ring 3,5-H), 7.58-7.56 (3- phenyl ring 2,6-H), 6.94-6.92 (2H, 9- phenyl ring 3,5-H)

¹³CNMR(400M,CDCl₃) δ (ppm): 182.8 (1-CO), 173.3 (3-CO), 170.4 (9-C=N-), 161.8 (9-N=C-), 158.3 (9- phenyl ring 4-C), 137.7 (3- phenyl ring 1-C), 130.6 (3- phenyl ring 4-C), 129.9 (3- phenyl ring 2,6- C), 127.5 (9- phenyl ring 1-C), 125.5-125.4 (3- phenyl ring 3,5-C), 114.6-114.3 (9- phenyl ring 3,5-C), 55.3 (9- OCH₃),50.4(6-OCH₃),40.3(3-CH₂)

Embodiment 92 3- descladinosylation -3-O- (3,4,5- trifluoro phenylacetyl group) -9- (4- methoxybenzylidene hydrazone) The preparation of clarithromycin (SIPI8557)

The same SIPI8554 of preparation method, 2 '-O- acetyl group -3- descladinosylation -3- hydroxyl -9- (4- methoxybenzene methylenes Base hydrazone) clarithromycin (1.52g, 2mmol) feeds intake to obtain product 0.65g (yield 36.5%, HPLC purity 91.7%).MS(ESI⁺, m/e):894.40[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 8.25 (s, 1H, 9-N=CH-), 7.71-7,69 (2H, 9- phenyl ring 2,6- ), H 7.19 (m, 1H, 3- phenyl ring 6-H), 6.95-6.89 (m, 3H, 9- phenyl ring 3,5-H, 3- phenyl ring 3-H)

¹³CNMR(400M,CDCl₃) δ (ppm): 182.7 (1-CO), 173.3 (3-CO), 169.7 (9-C=N-), 161.8 (9-N=C-), 158.3 (9- phenyl ring 4-C), 130.6-105.2 (3,9- phenyl ring C), 55.3 (9-OCH₃),50.5(6-OCH₃), 40.3(3-CH₂)

Embodiment 93 3- descladinosylation -3-O- (3,5- difluoro phenylacetyl group) -9- (4- methoxybenzylidene hydrazone) gram Draw the preparation of mycin (SIPI8558)

The same SIPI8554 of preparation method, 2 '-O- acetyl group -3- descladinosylation -3- hydroxyl -9- (4- methoxybenzene methylenes Base hydrazone) clarithromycin (1.52g, 2mmol) feeds intake to obtain product 0.67g (yield 38.4%, HPLC purity 91.6%).MS(ESI⁺, m/e):876.43[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 8.26 (s, 1H, 9-N=CH-), 7.72-7,69 (2H, 9- phenyl ring 2,6- ), H 6.96-6.87 (m, 4H, 9- phenyl ring 3,5-H, 3- phenyl ring 2,6-H), 6.71 (1H, 3- phenyl ring 4-H)

¹³CNMR(400M,CDCl₃) δ (ppm): 182.7 (1-CO), 173.3 (3-CO), 170.0 (9-C=N-), 161.8 (9-N=C-), 158.3 (9- phenyl ring 4-C), 137.2 (3- phenyl ring 1-C), 129.7 (9- phenyl ring 2,6-C), 127.5 (9- phenyl ring 1- C), 114.6-102.8 (3- phenyl ring C), 55.3 (9-OCH₃),50.4(6-OCH₃),40.3(3-CH₂)

The preparation of embodiment 94 3- descladinosylation -3- hydroxyl -9- (4- fluorobenzylidene hydrazone) clarithromycin

3- descladinosylation -3- hydroxyl -9- hydrazone clarithromycin (SIPI8903) (12g, 20mmol) is dissolved in 36mL methanol, adds Enter 4- fluorobenzaldehyde (3.2mL, 30mmol), glacial acetic acid (1.7mL, 30mmol), 65 DEG C are heated to reflux 4h.Methylene chloride is added 40mL, water 40mL adjust pH to 10, liquid separation with 3N sodium hydroxide, and water layer is extracted with 10mL methylene chloride, merges methylene chloride Layer, washing are evaporated to obtain crude product 13.5g after saturated sodium-chloride is dry, 1g column chromatography for separation are taken to obtain product 0.43g, yield 48.4%. MS(ESI⁺,m/e):710.88[M+H]⁺

Embodiment 95 2 '-O- acetyl group -3- descladinosylation -3- hydroxyl -9- (4- fluorobenzylidene hydrazone) clarithromycin Preparation

3- descladinosylation -3- hydroxyl -9- (4- fluorobenzylidene hydrazone) clarithromycin crude product (12.0g, 20mmol) is dissolved in 20mL methylene chloride is added acetic anhydride (5.6mL, 60mmol), 25 DEG C of stirring 4h.Add water 40mL, adjusts pH with 3N sodium hydroxide To 10, liquid separation, water layer is extracted with 10mL methylene chloride, merges dichloromethane layer, and washing is evaporated slightly after saturated sodium-chloride is dry Product 13.6g, crude yield 107.1%.

Embodiment 96 3- descladinosylation -3-O- (4- trifluoromethyl phenylacetyl group) -9- (4- fluorobenzylidene hydrazone) carat The preparation of mycin (SIPI8559)

2 '-O- acetyl group -3- descladinosylation -3- hydroxyl -9- (4- fluorobenzylidene hydrazone) clarithromycin (1.5g, It 2mmol) is dissolved in methylene chloride 10mL, is added 4- trifluoromethyl phenylacetic acid (0.96g, 4mmol), EDCI (0.79g, 4mmol), Glacial acetic acid (0.23mL, 4mmol), 25 DEG C of stirring 16h.Be added methylene chloride 10mL, water 20mL, with 3N sodium hydroxide adjust pH to 10, liquid separation, water layer is extracted with 10mL methylene chloride, merges dichloromethane layer, and washing is evaporated after saturated sodium-chloride is dry, is added Methanol 10mL, 65 DEG C be heated to reflux 4h after be evaporated, FLASH column chromatography for separation obtains product 0.65g (yield 36.3%, HPLC purity 80.9%).MS(ESI⁺,m/e):896.51[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 8.27 (s, 1H, 9-N=CH-), 7.77-7.73 (m, 2H, 9- phenyl ring 2, 6-H), 7.59-7.45 (m, 4H, 3,9- phenyl ring 3,5-H), 7.13-7.07 (m, 2H, 3- phenyl ring 2,6-H), 3.76-3.66 (m, 2H,3-COCH₂-),2.87(s,3H,6-OCH₃)

¹³CNMR(400M,CDCl₃) δ (ppm): 173.4 (3-CO), 170.4 (9-C=N-), 165.6 (9- phenyl ring 4-C), 157.4 (9-N=C-), 137.7-115.5 (3,9- phenyl ring C, 3-CF₃),50.5(6-OCH₃),41.1(3-CH₂)

Embodiment 97 3- descladinosylation -3-O- (3,4,5- trifluoro phenylacetyl group) -9- (4- fluorobenzylidene hydrazone) carat The preparation of mycin (SIPI8560)

Preparation method same SIPI8559,2 '-O- acetyl group -3- descladinosylation -3- hydroxyl -9- (4- fluorobenzylidene hydrazone) Clarithromycin (1.5g, 2mmol) feeds intake to obtain product 0.6g (yield 34.3%, HPLC purity 93.4%) MS (ESI⁺,m/e): 882.55[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 8.27 (s, 1H, 9-N=CH-), 7.77-7.68 (m, 2H, 9- phenyl ring 2, 6-H), 7.22-6.89 (m, 4H, 9- phenyl ring 3,5-H, 3- phenyl ring 2,5-H), 3.71-3.60 (m, 2H, 3-COCH₂-),2.87(s, 3H,6-OCH₃)

¹³CNMR(400M,CDCl₃) δ (ppm): 173.4 (3-CO), 169.7 (9-C=N-), 165.6 (9- phenyl ring 4-C), 163.1 (3- phenyl ring 6-C), 157.5 (9-N=C-), 130.9-105.2 (3,9- phenyl ring C), 50.5 (6-OCH₃),33.6(3- CH₂)

Embodiment 98 3- descladinosylation -3-O- (3,5- difluoro phenylacetyl group) -9- (4- fluorobenzylidene hydrazone) carat is mould The preparation of plain (SIPI8561)

Preparation method same SIPI8559,2 '-O- acetyl group -3- descladinosylation -3- hydroxyl -9- (4- fluorobenzylidene hydrazone) Clarithromycin (1.5g, 2mmol) feeds intake to obtain product 0.51g (yield 30.0%, HPLC purity 89.3%).MS(ESI⁺,m/e): 864.51[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 8.27 (s, 1H, 9-N=CH-), 7.77-7.73 (m, 2H, 9- phenyl ring 2, 6-H), 7.12-6.69 (m, 5H, 9- phenyl ring 3,5-H, 3- phenyl ring 2,4,6-H), 3.65 (d, J=6.4Hz, 2H, 3-COCH₂-), 2.87(s,3H,6-OCH₃)

¹³CNMR(400M,CDCl₃) δ (ppm): 173.4 (3-CO), 170.0 (9-C=N-), 165.6-161.8 (9- phenyl ring 4-C, 3- phenyl ring 3,5-C), 157.4 (9-N=C-), 137.2-102.6 (3,9- phenyl ring C), 50.4 (6-OCH₃),40.8(3- CH₂)

The preparation of embodiment 99 3- descladinosylation -3- hydroxyl -9- (4- trifluoromethyl phenylethylene hydrazone) clarithromycin

3- descladinosylation -3- hydroxyl -9- hydrazone clarithromycin (SIPI8903) (12g, 20mmol) is dissolved in 36mL methanol, adds Enter 4- trifluoromethyl acetophenone (5.6g, 30mmol), glacial acetic acid (1.7mL, 30mmol), 65 DEG C are heated to reflux 4h.Dichloro is added Methane 40mL, water 40mL adjust pH to 10, liquid separation with 3N sodium hydroxide, and water layer is extracted with 10mL methylene chloride, merges dichloromethane Alkane layer, washing obtain crude product 13.8g after being evaporated after saturated sodium-chloride is dry, 1g column chromatography for separation are taken to obtain product 0.18g, yield 16.2%.MS(ESI⁺,m/e):774.44[M+H]⁺

100 2 '-O- acetyl group -3- descladinosylation -3- hydroxyl -9- (4- trifluoromethyl phenylethylene hydrazone) gram of embodiment Draw the preparation of mycin

3- descladinosylation -3- hydroxyl -9- (4- trifluoromethyl phenylethylene hydrazone) clarithromycin crude product (12g, It 15.5mmol) is dissolved in 20mL methylene chloride, is added acetic anhydride (5.6mL, 60mmol), 25 DEG C of stirring 4h.Add water 40mL, with 3N hydrogen Sodium oxide molybdena adjusts pH to 10, liquid separation, and water layer is extracted with 10mL methylene chloride, merges dichloromethane layer, washing, and saturated sodium-chloride is done Crude product 13.2g, crude yield 107.9% are evaporated to obtain after dry.

Embodiment 101 3- descladinosylation -3-O- (4- chloro acetyl) -9- (4- trifluoromethyl phenylethylene hydrazone) gram Draw the preparation of mycin (SIPI8562)

2 '-O- acetyl group -3- descladinosylation -3- hydroxyl -9- (4- trifluoromethyl phenylethylene hydrazone) clarithromycin (1.6g, 2mmol) is dissolved in methylene chloride 10mL, is added 4- chlorobenzene acetic acid (0.68g, 4mmol), EDCI (0.79g, 4mmol), Glacial acetic acid (0.23mL, 4mmol), 25 DEG C of stirring 16h.Be added methylene chloride 10mL, water 20mL, with 3N sodium hydroxide adjust pH to 10, liquid separation, water layer is extracted with 10mL methylene chloride, merges dichloromethane layer, and washing is evaporated after saturated sodium-chloride is dry, is added Methanol 10mL, 65 DEG C be heated to reflux 4h after be evaporated, FLASH column chromatography for separation obtains product 0.25g (yield 13.5%, HPLC purity 80.6%).MS(ESI⁺,m/e):926.54[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.98-7.96 (2H, 9- phenyl ring 2,6-H), 7.67-7.65 (2H, 9- benzene Ring 3,5-H), 7.31-7.26 (4H, 3- phenyl ring 2,3,4,6-H), 3.38 (2H, 3-COCH₂-),2.39(s,3H,6-OCH₃)

Embodiment 102 3- descladinosylation -3-O- (4- trifluoromethyl phenylacetyl group) -9- (4- trifluoromethyl phenylethylene Hydrazone) clarithromycin (SIPI8563) preparation

(4- trifluoromethylbenzene is sub- by preparation method same SIPI8562,2 '-O- acetyl group -3- descladinosylation -3- hydroxyl -9- Ethyl hydrazone) clarithromycin (1.6g, 2mmol) feeds intake to obtain product 0.43g (yield 22.4%, HPLC purity 94.6%).MS(ESI⁺,m/e):960.52[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.98-7.96 (2H, 9- phenyl ring 2,6-H), 7.67-7.65 (2H, 9- benzene Ring 3,5-H), 7.60-7.49 (4H, 3- phenyl ring 2,3,4,6-H), 3.38 (2H, 3-COCH₂-),2.39(s,3H,6-OCH₃)

Embodiment 103 3- descladinosylation -3-O- (3,4,5- trifluoro phenylacetyl group) -9- (4- trifluoromethyl phenylethylene Hydrazone) clarithromycin (SIPI8564) preparation

(4- trifluoromethylbenzene is sub- by preparation method same SIPI8562,2 '-O- acetyl group -3- descladinosylation -3- hydroxyl -9- Ethyl hydrazone) clarithromycin (1.6g, 2mmol) feeds intake to obtain product 0.35g (yield 18.5%, HPLC purity 97.1%).MS(ESI⁺,m/e):946.51[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.98-7.96 (2H, 9- phenyl ring 2,6-H), 7.67-7.65 (2H, 9- benzene Ring 3,5-H), 7.18 (1H, 3- phenyl ring 3-H), 6.95 (1H, 3- phenyl ring 3-H), 3.40 (2H, 3-COCH₂-),2.38(s,3H,6- OCH₃)

Embodiment 104 3- descladinosylation -3-O- (3,5- difluoro phenylacetyl group) -9- (4- trifluoromethyl phenylethylene Hydrazone) clarithromycin (SIPI8565) preparation

(4- trifluoromethylbenzene is sub- by preparation method same SIPI8562,2 '-O- acetyl group -3- descladinosylation -3- hydroxyl -9- Ethyl hydrazone) clarithromycin (1.6g, 2mmol) feeds intake to obtain product 0.63g (yield 34.1%, HPLC purity 80.7%).MS(ESI⁺,m/e):928.53[M+H]⁺

¹HNMR(400MHz,CDCl₃) δ (ppm): 7.99-7.96 (2H, 9- phenyl ring 2,6-H), 7.67-7.65 (2H, 9- benzene Ring 3,5-H), 6.91-6.90 (2H, 3- phenyl ring 2,6-H), 6.72 (1H, 3- phenyl ring 4-H), 3.38 (2H, 3-COCH₂-),2.39 (s,3H,6-OCH₃)。

Effect example 1 is using MRSA ATCC43300 as mode bacterium, and by extracorporeal bacteria inhibitor test measurement and preliminary screening has There is the compound of potential bacteriostatic activity or synergistic activity.

1. experimental material

(1) bacterial strain methicillin-resistant staphylococcus aureus MRSA ATCC43300, mecA is positive；It is tried according to CLSI clinic Standard inspection is quasi-, and oxacillin MIC method is used to detect the percentage of methicillin-resistant of mecA mediation.Therefore oxacillin will be used to be used for subsequent Experiment.The compound of various concentration and oxacillin are combined in experiment, detect the MIC value to ATCC43300.

(2) reagent and solution are prepared

Culture medium: LB liquid medium (g/L):

LB solid medium (g/L): yeast powder 5, tryptone 10, sodium chloride (NaCl) 10, agar powder 20；

MH fluid nutrient medium (g/L): beef extract 2.0, soluble starch 1.5, acid hydrolyzed casein 17.5, sodium chloride (NaCl) 6.0, sodium hydroxide (NaOH) adjusts pH to 7.2-7.4.Reagent, medium component and source are shown in Table 1

1 reagent of table, medium component and source table

Title	Source
		DMSO	This Science and Technology Ltd. of Beijing health times
Ethyl alcohol	Sinopharm Chemical Reagent Co., Ltd.
		Glucose	Sinopharm Chemical Reagent Co., Ltd.
Agar powder	Beijing DingGuo ChangSheng Biology Technology Co., Ltd
		Yeast powder	Oxoid company of Britain
Tryptone	Oxoid company of Britain
		Beef extract	Zhejiang medicine Xinchang pharmaceutical factory
Soluble starch	Sinopharm Chemical Reagent Co., Ltd.
		Beef extract	Zhejiang medicine Xinchang pharmaceutical factory

(3) 0.5% Maxwell opacity tube preparation method is as follows:

0.048mol BaCl₂(1.17%W/V BaCl₂·2H₂O)0.5ml

0.18mol H₂SO4 (1%, V/V) 99.5ml

Two liquid are set in ice-water bath and are mixed after cooling, are set in screw-cap test tube, the preservation of room temperature dark place are put, with preceding mixing.

(5) instrument and equipment

H1650-W table model high speed centrifuge, Xiang Yi centrifuge Instrument Ltd.；

ZHWY-200B constant temperature culture oscillator, Shanghai Zhi Cheng analysis instrument Manufacturing Co., Ltd.

2. experimental method

(1) test tube meat soup coubling dilution measures MIC value

It tests bacteria suspension to prepare: drawing MRSA ATCC43300 bacteria suspension from the glycerol tube of -70 DEG C of preservations and press 1:1000 Ratio be inoculated in 37 DEG C of 4~6h of culture in 3~5mLM-H meat soup, then by same ratio switching 37 in 2mL M-H meat soup DEG C culture 16h-20h, then by bacterium solution with 0.5% Maxwell opacity tube than turbid, adjust turbidity and standard ratio with sterile saline (its bacterial concentration is equivalent to 10 after turbid pipe is identical⁸CFU/ml), then with M-H meat soup by 1: 200 dilution, and it is inscribed in 15min Kind, for measuring drug MIC experiment.

Measurement for single antibiotic MIC value: sterile test tube (10 × 100mm) 10 is taken, MH is added in the 1st test tube Culture medium (volume V₁) and corresponding antibiotic storing liquid (volume V₂) making 400 μ L of its final volume, remaining every pipe is added 200 μ L MH culture mediums.V₂It is determined by the concentration of antibiotic, sets in the 1st pipe at this time antibiotic concentration as A μ g/mL.After mixing 200 μ L to the 2nd pipe is drawn from the 1st pipe, draws 200 μ L to the 3rd pipe after mixing again, so continuous doubling dilution to the 10th pipe, And 200 μ L are drawn from the 10th pipe and are discarded.Using the bacterium grown in the MH culture medium of not drug containing as positive control, bacterium is not added Culture medium is as negative control.

Above-mentioned each 200 μ L of the experiment bacteria suspension prepared is added in every pipe, making the final bacterial concentration of every pipe is about 0.25- 0.5×10⁶CFU/mL.1st pipe to the 10th pipe drug concentration is respectively 1/2A, 1/4A, 1/8A, 1/16A, 1/32A, 1/64A, 1/ 128A、1/256A、1/512A、1/1024Aμg/mL。

When noval chemical compound and beta-lactam antibiotic drug combination, used beta-lactam antibiotic MIC value Measurement: generally by the compound as shown in Equation 1, the salt of compound as shown in Equation 1, such as 1 ' compound represented of formula or The salt of 1 ' compound represented of formula be fixed on certain concentration (final concentration be generally as described in compound as shown in Equation 1, such as formula 1 The salt of compound represented, such as 1 ' compound represented of formula or such as the salt of 1 ' compound represented of formula individually to the test bacterium MIC 1/4 times of value, i.e., described compound as shown in Equation 1, the salt of compound as shown in Equation 1, such as 1 ' compound represented of formula Or if the salt of 1 ' compound represented of formula is to 0.25 × MIC of MRSA ATCC43300), it is added in culture medium, according still further to list The measuring method of one antibiotic MIC value successively dispenses, by beta-lactam antibiotic doubling dilution to be determined.Test tube is placed in In 37 DEG C of shaking tables, 250rpm observes the growing state of bacterium after cultivating 18h~20h.Test tube is taken out, light is observed one by one, it is all The drug minimum concentration i.e. testing drug of bacterial growth is visible by naked eyes as the minimum inhibitory concentration (MIC) to bacterium to be measured, and with MIC reports it.

(2) statistical analysis

The above experiment is repeated 3 times, and experimental result uses data between t-test group to carry out significance difference analysis.P value < 0.05 has significant difference.

3. experimental result

The part macrolides compound of the invention of table 2 and oxacillin are combined the MIC (μ of anti-MRSA ATCC43300 g/mL)

The part macrolides compound of the invention of table 3 and oxacillin are combined the MIC (μ of anti-MRSA ATCC43300 g/mL)

Effect example the results showed that utilizing Caenorhabditis elegans --- methicillin-resistant S grape ball Bacterium infection model is found, macrolide noval chemical compound such as SIPI8294 and benzene when screening the reactive compound of antimicrobial agent infection The survival rate that can significantly improve MRSA infection nematode is used in combination in azoles XiLin, and activity is better than vancomycin.

External synergism test Preliminary Results show that the macrolide noval chemical compound of this researching and designing synthesis can be significant Oxacillin is reduced to the MIC of MRSA ATCC43300, wherein representation compound SIPI8294 can be reduced respectively to some extent Kind beta-Lactam antibiotic has universal synergistic effect to the MIC of MRSA ATCC43300.And the macrolide of clinical use is anti- Raw element (azithromycin, clarithromycin, erythromycin, roxithromycin, Ketek, thiophene erythromycin) and beta-lactamase inhibitor (Tazobactam Sodium, clavulanic acid) external not similar synergistic effect.

Design has synthesized a series of macrolides compounds.External synergism test shows in the acyl of all design synthesis Esters noval chemical compound under 2 μ g/mL concentration, can be such that the MIC of oxacillin reduces by a relatively large margin when being combined with oxacillin, Show specific synergistic effect, activity is better than compound SIPI8294.

This result of study, which means that Novel macrocyclic lactone derivatives are combined with clinical existing beta-Lactam antibiotic, to be made With, can for reply MRSA infection potential new way be provided.Since this kind of noval chemical compound itself is there are few antibacterial activity, it is not easy to make Generate drug resistance at the survival pressure of bacterium, thus to bacterial drug resistance lead to the problem of and crossing drug resistant may have weight The meaning wanted.

Extracorporeal bacteria inhibitor test shows and (is shown in Table 3), the noval chemical compound of all optimization designs synthesis, when being combined with oxacillin, Under 2 μ g/ml concentration, the MIC of oxacillin can be made to have to be reduced by a relatively large margin, shows specific synergistic effect.In addition to chemical combination The synergistic effect of object SIPI8411 is slightly lower outer, and the synergistic activity of all acyl lactone class compounds is superior to compound SIPI8294.

Claims

1. a kind of macrolides compound 1 ' or its salt,

Any compound that the macrolides compound 1 ' is as follows,

2. a kind of macrolides compound 1 or its salt,

Any compound that the macrolides compound 1 is as follows,

3. the preparation method of macrolides compound 1 ' as described in claim 1 or its salt, it is characterised in that:

It willOne or both of with compound 1 ' -12 carry out condensation reaction, changed Close object 1 ' -13；

Wherein, the compound 1 ' -13 is macrolides compound 1 '.

4. the preparation method of macrolides compound 1 as claimed in claim 2 or its salt, it is characterised in that: described is big The preparation method of macrolides 1 obtains compound 1-18 the following steps are included: by compound 1-17 progress alcoholysis reaction ?；

Wherein, the compound 1-18 is macrolides compound 1 as stated in claim 2, but is not

5. the preparation method of macrolides compound 1 ' as claimed in claim 3 or its salt, it is characterised in that: the change The preparation method for closing object 1 ' -13, carries out, in a solvent or under the conditions of solvent-free when the preparation side of the compound 1 ' -13 When method carries out in a solvent, the solvent is alcohols solvent and/or halogenated hydrocarbon solvent, when the compound 1 ' -13 When preparation method carries out in a solvent, the volume mass ratio of the solvent and the compound 1 ' -12 be 1mL/g~ 100mL/g；DescribedOne or both of rub with the compound 1 ' -12 Your ratio is 0.5~10；30 DEG C~100 DEG C of the temperature of the condensation reaction.

6. the preparation method of macrolides compound 1 as claimed in claim 4 or its salt, it is characterised in that: in preparationization In the method for closing object 1-18, the solvent is alcohols solvent；The volume mass of the solvent and the compound 1-17 Than for 1mL/g~100mL/g；The temperature of the alcoholysis reaction is 20 DEG C~100 DEG C.

7. the salt of macrolides compound 1 ' as described in claim 1 or the macrolides compound 1 ' or such as The salt of macrolides compound 1 as claimed in claim 2 or the macrolides compound 1 is in preparation synergy β-interior acyl Amine antibiotic is to the application in the drug of the inhibiting effect of methicillin-resistant staphylococcus aureus.

8. a kind of pharmaceutical composition, it is characterised in that: including macrolides compound 1 ' as described in claim 1, such as weigh Benefit require 1 described in the salt of macrolides compound 1 ', macrolides compound as claimed in claim 21 and as weighed Benefit require 2 described in macrolides compound 1 one of salt or a variety of and beta-lactam antibiotic.

9. pharmaceutical composition as claimed in claim 8, it is characterised in that: in the pharmaceutical composition, in the big ring Ester type compound 1, the macrolides compound 1 ', the macrolides compound 1 salt and the big ring The mass percentage of the salt of lactone compound 1 ' is 0.5%~99%, and the mass percentage is the big ring Lactone compound 1, the macrolides compound 1 ', the salt of the macrolides compound 1 and described big The salt of macrolides 1 ' accounts for the percentage of the pharmaceutical composition gross mass；The beta-lactam antibiotic Mass percentage be 1%~99.5%, the mass percentage is the quality of beta-lactam antibiotic, is accounted for described Pharmaceutical composition gross mass percentage, the summation of the mass fraction of each component is 100% in the pharmaceutical composition.

10. pharmaceutical composition as claimed in claim 9, it is characterised in that: in the pharmaceutical composition, in the big ring Ester type compound 1, the macrolides compound 1 ', the macrolides compound 1 salt and the big ring The mass percentage of the salt of lactone compound 1 ' is 50%~97%；The quality percentage of the beta-lactam antibiotic Content is 3%~50%.

11. pharmaceutical composition as claimed in claim 8, it is characterised in that: in the pharmaceutical composition, the interior acyl of the β- Amine antibiotic be penicillin antibiotics, cephalosporins, carbapenem antibiotic, cephamycin-type antibiotic and One of monocycle beta-lactam antibiotics are a variety of.

12. pharmaceutical composition as claimed in claim 11, it is characterised in that: in the pharmaceutical composition, the mould Plain class antibiotic be penicillin, benzyl penicillin, Benzylpenicillin sodium salt, ospeneff, ampicillin, ampicillin, carbenicillin sodium, Oxacillin, Cloxacillin, dicloxacillin, flucloxacillin, Benzathine, Furbucillin, Amoxicillin, mezlocillin, how One of husband XiLin, Ticarcillin, azlocillin, Piperacillin and Mecillinam are a variety of；The cephalosporins antibiosis Element is cefalexin, Cefotiam, cefadroxil, cephazoline, cefradine, Cefaclor, cefuroxime, cephalo The appropriate human relations pivoxil of amine, cefathiamidine, Cefprozil, ceftriaxone, cephalo, Cefodizime, Cefetamet Pivoxil, Cefixime, cephalo It moors oxime ester, cefotaxime, cefotaxime potassium, Cefdinir, cephalo and draws oxygen, ceftezole, cefotaxime, cefoperazone, cephalo One of thiophene, Cefamandole, Cefpirome, Cefepime and Cefuzonam are a variety of；The Carbapenems antibiosis Element is one of Imipenem, Meropenem and Panipenem or a variety of；The cephamycin-type antibiotic be Cefoxitin, One of cefoxitin sodium, cefmetazole, cefmetazole sodium, cefotetan and Cefminox are a variety of；The monocycle β- Lactam antibiotics are aztreonam.

13. pharmaceutical composition as claimed in claim 8, it is characterised in that: macrolides compound as shown in Equation 1, such as Macrolides compound shown in formula 1 ', the salt of macrolides compound as shown in Equation 1 and the big ring as shown in formula 1 ' The mass ratio of the gross mass of the salt of lactone compound and the beta-lactam antibiotic is >=1:1；

And/or

It is the macrolides compound as shown in Equation 1, macrolides compound shown in 1 ', as shown in Equation 1 big In the solution that the salt of the salt of macrolides and the macrolides compound as shown in formula 1 ' and water are formed, it is described as Macrolides compound shown in formula 1, macrolides compound shown in 1 ', macrolides chemical combination as shown in Equation 1 The gross mass of the salt of the salt of object and the macrolides compound as shown in formula 1 ' and ratio >=8ug/mL of liquor capacity.

14. as the described in any item pharmaceutical compositions of claim 8~13 inhibit methicillin-resistant staphylococcus grape ball in preparation Application in the drug of bacterium.

15. application as claimed in claim 14, it is characterised in that: the methicillin-resistant staphylococcus aureus is resistance to first Oxygen XiLin staphylococcus aureus mode bacterium.

16. application as claimed in claim 15, it is characterised in that: the methicillin-resistant staphylococcus aureus mode bacterium For ATCC43300.